Inflammation Research[JOURNAL]
Sun
200 papers
Spleen-associated macrophage alterations and embryo viability in a murine model of recurrent spontaneous abortion.
Zhu K, Zhang H, Chen S … +6 more , Deng X, Chen X, Wan D, Zhu M, Zhang C, Gao Y
Inflamm Res · 2026 Jul · PMID 42401784 · Publisher ↗
BACKGROUND: Recurrent spontaneous abortion (RSA) is commonly attributed to immune dysregulation at the maternal-fetal interface. The contribution of the spleen, as a peripheral immune organ, remains unclear. This study i...
BACKGROUND: Recurrent spontaneous abortion (RSA) is commonly attributed to immune dysregulation at the maternal-fetal interface. The contribution of the spleen, as a peripheral immune organ, remains unclear. This study investigated spleen-associated immune alterations in a murine model of RSA. METHODS: An RSA model was established by mating CBA/J females with DBA/2 males. Splenic and decidual immune-cell distributions were assessed by histology, flow cytometry, and cytokine analysis. Splenectomy and macrophage depletion were performed as experimental interventions. Decidual transcriptomic changes following splenectomy were analyzed by bulk RNA sequencing and transcriptomic enrichment analyses. RESULTS: RSA mice exhibited splenomegaly, altered splenic histological features, and changes in splenic immune-cell composition, including increased numbers of Ly6C CX3CR1 macrophages. Decidual immune alterations mirrored several changes observed in the spleen. Splenectomy was associated with increased embryo viability, reduced histological alterations, and changes in decidual immune-cell distributions. Similar effects on embryo viability and decidual immune-cell distributions were observed following effective macrophage depletion. Transcriptomic analyses of decidual tissue following splenectomy identified transcriptional differences involving mitochondrial-associated, Wnt-related, and protein synthesis-associated pathways. CONCLUSION: These findings identify an association between spleen-associated immune alterations and RSA and suggest that splenectomy is accompanied by changes in decidual immune-cell distributions, tissue-level transcriptional patterns, and embryo viability.
Chronic intermittent hypoxia sustains the low-grade inflammatory memory of monocytes via activation of myelopoiesis.
Li SQ, Wang Y, Li MY … +7 more , Zhang L, Chen XX, Lin YN, Zhou LN, Sun XW, Ding YJ, Li QY
Inflamm Res · 2026 Jul · PMID 42400619 · Publisher ↗
OBJECTIVE: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), drives a chronic low-grade inflammatory state linked to multiple comorbidities. Monocytes play a pivotal role in the regulati...
OBJECTIVE: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), drives a chronic low-grade inflammatory state linked to multiple comorbidities. Monocytes play a pivotal role in the regulation of inflammatory responses. This study aimed to characterize the inflammatory profile of monocytes induced by CIH. METHODS: Distribution and activation status of monocytes were analyzed in OSA versus healthy controls. In vivo, models of CIH were employed to assess the immediate and long-term effects on monocyte inflammatory profiles and bone marrow (BM) myelopoiesis. RESULTS: Monocytes derived from OSA patients exhibited enhanced activation marker expression and cytokine secretion. In vivo, CIH provoked immediate inflammatory responses of peripheral monocytes, accompanied by increased abundance of hematopoietic stem and progenitor cells in the BM, resulting in enhanced myelopoiesis and increased circulating monocytes. After normoxic recovery, monocytes from CIH-exposed mice exhibited heightened inflammatory responses upon secondary challenge, which was associated with sustained, myeloid-biased myelopoiesis in the BM. CONCLUSIONS: Our findings demonstrate that CIH sustains a low-grade inflammatory memory in monocytes, characterized by both basal activation and enhanced responsiveness to secondary stimulation. We identify the establishment of maladaptive myelopoiesis as a novel mechanism for the sustained inflammatory state in OSA, providing new insights into the pathogenesis of inflammatory responses and comorbidities associated with OSA.
Single-cell profiling reveals clonal CD8T cell-derived IFNγ drives Sjögren's disease-related dacryoadenitis.
Zhu HX, Li FF, Chen XM … +5 more , Zhang BY, Xu T, Lian ZX, Gao CY, Meng QL
Inflamm Res · 2026 Jul · PMID 42397411 · Publisher ↗
BACKGROUND: Sjögren's disease (SjD) is a chronic progressive autoimmune disorder primarily affecting the exocrine glands. Dacryoadenitis represents one of the typical clinical manifestations of SjD, yet its underlying pa...
BACKGROUND: Sjögren's disease (SjD) is a chronic progressive autoimmune disorder primarily affecting the exocrine glands. Dacryoadenitis represents one of the typical clinical manifestations of SjD, yet its underlying pathogenic mechanisms remain poorly understood. This study investigated the immune microenvironment of the lacrimal gland to elucidate the pathogenic cell subset and key molecular factors driving SjD-related dacryoadenitis. METHODS: Aire mice, a well-established SjD-related dacryoadenitis model, were employed in this study. Lacrimal gland infiltrating immune cells were profiled by single-cell RNA sequencing and flow cytometry. The T-cell repertoire of lacrimal gland T cells was characterized by single-cell T cell receptor (TCR) sequencing. IfngAire mice were used to evaluate the roles of IFNγ in SjD-related dacryoadenitis model. The immunologic profiles and histopathological changes of the lacrimal gland were assessed in Aire mice with or without IFNγ deficiency. RESULTS: We identified a clonally expanded population of CCL5CD8 memory T cells with high expression of cytotoxic effector molecules that is in spatial proximity to acinar cells. IFNγ derived from CCL5CD8memory T cells acts on multiple cell types, upregulating costimulatory molecules and chemokines within the lacrimal gland. Notably, either CD8 T cell deletion or IFNγ knockout resulted in a marked attenuation of inflammatory infiltration and acinar atrophy within the lacrimal glands of Aire mice. CONCLUSIONS: IFNγ derived from clonally expanded CCL5CD8memory T cells drives the pathogenesis of SjD-related dacryoadenitis, supporting IFNγ blockade as a potential therapeutic strategy for SjD-related dacryoadenitis.
From acute mast cell activation to a structured immunothrombotic and autoimmune niche in chronic spontaneous urticaria.
Criado PR, Fachini Jardim Criado R, Martinez Zugaib Abdalla B
Inflamm Res · 2026 Jul · PMID 42393364 · Publisher ↗
BACKGROUND: Chronic spontaneous urticaria (CSU) presents recurrent wheals and/or angioedema for more than six weeks without an identifiable trigger. Although mast cell activation and histamine release are well-establishe...
BACKGROUND: Chronic spontaneous urticaria (CSU) presents recurrent wheals and/or angioedema for more than six weeks without an identifiable trigger. Although mast cell activation and histamine release are well-established effector mechanisms, this model does not explain disease persistence, immune dysregulation, or treatment refractoriness. A deeper mechanistic framework is required to explain progression to chronic disease. PURPOSE: To propose a stage-wise CSU chronification model, reframing the disease as a structured dermal immunothrombotic and autoimmune niche rather than an episodic mast cell-effector event, and to derive therapeutic implications. METHODS: A narrative synthesis of ultrastructural, immunohistochemical, transcriptomic, and clinical evidence from the published clinical literature, including original studies from our group on acute drug-induced urticaria and antihistamine-refractory CSU was performed. RESULTS: Five sequential stages drive chronification: (1) FcεRI/BTK-dependent mast cell degranulation; (2) eosinophil tissue-factor activation of the coagulation-complement loop; (3) FXIIIa⁺ dendrocyte phagocytosis and T-cell priming via OX40/OX40L; (4) Th2-driven M2 macrophage polarization with autoantibody-mediated mast cell reactivation; and (5) JAK/STAT and IFN-λ1 signaling sustaining dermal immune niche. Transcriptomic hub genes and cytokine profiling further support this model. CONCLUSION: CSU reflects a structured immune architecture rather than isolated mast cell activation. This explains treatment refractoriness and supports targeting upstream checkpoints, including BTK, JAK, and OX40/OX40L for sustained control.
Lipopolysaccharide promotes rheumatoid arthritis by enhancing Wnt7b mediated macrophage-FLS communication.
Wang B, Song Y, Xu W … +10 more , Chen J, Huang Y, Zhou X, Cai Y, Xia A, Li Y, Jiang L, Liao F, Huang J, Miao C
Inflamm Res · 2026 Jul · PMID 42393256 · Publisher ↗
BACKGROUND: Our previous research has shown that lipopolysaccharide (LPS) derived from Gram-negative bacteria in the intestine promoted rheumatoid arthritis (RA) after entering peripheral blood, but the specific molecula...
BACKGROUND: Our previous research has shown that lipopolysaccharide (LPS) derived from Gram-negative bacteria in the intestine promoted rheumatoid arthritis (RA) after entering peripheral blood, but the specific molecular mechanism was unclear. METHOD: This study used transcriptome and proteomic sequencing, western blotting, co-immunoprecipitation (Co-IP), cell co-culture, and other related methods to investigate whether LPS entering peripheral blood activated the Wnt7b secretion in macrophages, and used the Wnt7b as a messenger molecule to promote the communication between macrophage-fibroblast-like synoviocyte (FLSs), ultimately leading to the onset of RA. RESULT: The results showed that LPS significantly promoted the pathology of collagen induced arthritis (CIA) mice. Transcriptome and proteomic sequencing, as well as experimental validation, confirmed that the target of LPS may be the Wnt7b. Knocking down the Wnt7b in CIA mice could effectively alleviate the LPS induced pathology. Furthermore, in the M macrophage-FLS co-culture system, overexpression of Wnt7b in M macrophages promoted the expression of RA pathological factors in FLSs and activated the WNT/CTNNB1 signaling pathway of FLSs. However, knocking down the Wnt7b in M macrophages resulted in the opposite effects. Interestingly, in the M macrophage-FLS co-culture system, overexpression of Wnt7b in M macrophages could enhance the expression of frizzled class receptor 8 (FZD8) on FLSs, activating the Wnt/β-catenin signaling pathway of FLSs. However, knocking down the FZD8 in FLSs after overexpression of Wnt7b could interfere with the effects of overexpression of Wnt7b. In addition, adding LPS to M macrophages promoted the FZD8 expression of co-cultured FLSs and activated the Wnt/β-catenin signaling pathway. Knocking down FZD8 in FLSs after adding LPS to M0 macrophages could interfere with the effects of LPS. CONCLUSION: This study suggested that circulating LPS stimulated macrophages to secrete Wnt7b, which acted as a messenger molecule and bound to the FZD8 receptor on the FLSs cell membrane in the synovial microenvironment, promoting the activation of the Wnt/β-catenin signaling pathway in FLSs and leading to RA.
Unanswered questions on palmitic acid-driven neuroimmune inflammation in atopic dermatitis: a commentary on Chen et al.
Jiang B, Liu H
Inflamm Res · 2026 Jul · PMID 42384050 · Publisher ↗
This commentary provides a critical appraisal of the recent study by Chen and colleagues, which demonstrated that cutaneous palmitic acid (PA) aggravates atopic dermatitis (AD) by driving S-palmitoylation of transient re...
This commentary provides a critical appraisal of the recent study by Chen and colleagues, which demonstrated that cutaneous palmitic acid (PA) aggravates atopic dermatitis (AD) by driving S-palmitoylation of transient receptor potential vanilloid 1 (TRPV1) in sensory neurons and Mas-related G protein-coupled receptor B2 (MRGPRB2) in mast cells, with the serum/glucocorticoid regulated kinase 1 (SGK1)/neural precursor cell expressed developmentally downregulated protein 4-like (NEDD4L) axis serving as a critical contextual regulator. While the original study offers compelling in vivo genetic validation, several mechanistic and translational questions remain unresolved. Here, we prioritize three areas for future investigation: first, the upstream sources of elevated cutaneous PA-whether derived from keratinocyte lipogenesis, systemic circulation, or microbial production-remain undefined and warrant cell-type-specific genetic interrogation complemented by stable-isotope tracing, spatial lipidomics, and germ-free models. Second, the functional divergence of S-palmitoylation on TRPV1 (promoting degradation) versus MRGPRB2 (conferring stabilization) suggests involvement of distinct palmitoyl acyltransferases (PATs) or context-dependent effects; we propose testable hypotheses including the candidate PAT zDHHC4 for TRPV1 and advocate for cell-based reconstitution, cysteine-mutant rescue, and PAT screening approaches. Third, the anatomical divergence in spinal inflammation between nape and ear models raises questions about the generalizability of central neuroimmune engagement across AD phenotypes, with implications for preclinical model selection and clinical subset stratification. Addressing these questions will clarify whether the PA-palmitoylation-neuroimmune axis represents a tractable therapeutic target and will inform the development of precision interventions that interrupt this pathway without disrupting broader homeostatic palmitoylation, while recognizing that current lack of cell-type-specific palmitoylation inhibitors remains a major hurdle.
Pathway-level proteomics identifies subcellular trafficking dysregulation as a molecular signature in severe traumatic brain injury.
Van Nynatten LR, Tweddell D, Daley M … +4 more , Cepinskas G, Basmaji J, Slessarev M, Fraser DD
Inflamm Res · 2026 Jun · PMID 42373949 · Full text
BACKGROUND: Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide in intensive care units, yet no targeted neuroprotective therapies exist despite over 300 clinical trials. This therapeut...
BACKGROUND: Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide in intensive care units, yet no targeted neuroprotective therapies exist despite over 300 clinical trials. This therapeutic failure stems partly from biological heterogeneity and the limitations of single-biomarker approaches that cannot capture the multifaceted pathophysiology of secondary brain injury. Systems biology approaches examining dysregulated pathways rather than isolated proteins may reveal candidate endotypes suitable for patient stratification and identify potential therapeutic targets. METHODS: We conducted an exploratory, case-control study, in adult critically-ill patients comparing 10 severe TBI (sTBI) patients (median GCS 5.5) with 10 age-and sex-matched healthy controls. Plasma samples were collected upon admission to the ICU, within 24 h of injury. High-throughput proximity extension assays quantified 1196 plasma proteins, identifying multiple differentially expressed proteins. Gene set enrichment analysis interrogated Reactome pathways and Gene Ontology terms. Protein-protein interaction networks were constructed using the STRING database, and associations between enriched pathways and clinical variables were examined. RESULTS: We identified 348 significantly differentially abundant proteins between groups. Gene set enrichment analysis revealed 19 enriched Reactome pathways and 12 Gene Ontology terms, predominantly reflecting immune activation, inflammation, cellular stress responses, and intracellular trafficking. Strikingly, membrane trafficking pathways, including clathrin-mediated endocytosis and Golgi transport, emerged as significantly enriched, representing an underrecognized mechanism in sTBI pathophysiology. Protein-protein interaction analysis identified four functional clusters, with IL6 and IL10 as densely connected hub proteins coordinating inflammatory responses. Membrane trafficking pathways were associated with clinical outcomes including both length of hospital and intensive care unit stay, as well as need for neurosurgical intervention, in sTBI patients. CONCLUSIONS: By profiling the expression of 1196 plasma proteins in parallel, this study provides one of the most comprehensive proteomic characterizations of critically-ill adults with severe traumatic brain injury to date. Systems biology analyses suggest that sTBI may trigger coordinated pathway-level dysregulation extending beyond inflammation to include subcellular trafficking machinery. The association between membrane trafficking pathways and clinical outcomes suggests these may represent a candidate molecular endotype with prognostic relevance. These hypothesis-generating findings support pathway-based approaches for patient stratification and therapeutic targeting in sTBI, though validation in larger cohorts is required.
Endothelial cell-specific knockout of ATG5 ameliorates inflammation and renal fibrosis by regulating pyroptosis.
Huang Y, Wen S, Chen L … +12 more , Gao Y, Xu S, Fang C, Tang J, Yuan Y, Feng Y, Ma S, Luo S, Zhang Q, Shi X, Ruan X, Guo X
Inflamm Res · 2026 Jun · PMID 42371100 · Full text
OBJECTIVES: ATG5, a key regulator of autophagy-associated inflammation, is markedly upregulated under inflammatory conditions. In this study, we observed significantly elevated ATG5 expression in the kidneys of patients...
OBJECTIVES: ATG5, a key regulator of autophagy-associated inflammation, is markedly upregulated under inflammatory conditions. In this study, we observed significantly elevated ATG5 expression in the kidneys of patients with renal fibrosis and in mouse kidneys after unilateral ureteral obstruction (UUO), particularly in renal tubules and glomeruli. Recent studies suggest that enhanced ATG5-mediated autophagy in tubular epithelial cells targets the NF-κB pathway to alleviate renal injury. The glomerulus is a dense capillary network primarily composed of endothelial cells, which represent a key immune cell population in the kidney. However, whether endothelial ATG5 exerts a function similar to that of tubular ATG5 during the progression of renal fibrosis remains unclear. METHODS: First, Sirius red staining, immunohistochemistry staining and other and pathological methods were used to analyze the expression of ATG5 in relation to the progression of renal fibrosis in patients and UUO model mice. We next observed the effects of endothelial-specific knockout of ATG5 in mice with renal fibrosis induced by the UUO model by ultrasound image assessment, HE staining, and Masson staining. Human umbilical vein endothelial cells (HUVECs) were isolated, and their regulation of inflammation and promotion of renal fibrosis were analyzed by overexpression and knockdown of ATG5 using in vitro synthetic mRNA and siRNA interference techniques. Transmission electron microscopy (TEM), qPCR and Western blotting were used to determine the effect of endothelial ATG5 on promoting inflammation-dependent pyroptosis in vitro and in vivo. Finally, the expression of GSDMD, a key pyroptosis gene, was examined in the kidneys of clinical renal fiber patients by immunohistochemistry staining. RESULTS: We successfully generated endothelial-specific ATG5 knockout (Tek-Cre ATG5 KO) mice and found that endothelial cell deletion of ATG5 attenuated UUO-induced renal fibrosis. Mechanistically, endothelial-specific ATG5 knockout suppressed pyroptosis and the release of inflammatory factors in the UUO model, primarily by inhibiting GSDMD expression and its cleavage into the N-GSDMD fragment during canonical NLRP3 inflammasome activation. Electron microscopy results showed that ATG5 mainly caused pyroptosis independent of plasma membrane pores in endothelial cells. Conditioned medium from human umbilical vein endothelial cells with ATG5 knockdown inhibited the expression of the key fibrotic marker TGF-β1 in renal tubular epithelial HK-2 cells. Consistent results were obtained when HK-2 cells were cocultured with serum from UUO mice with endothelial-specific ATG5 knockout. Furthermore, GSDMD expression was positively correlated with the degree of fibrosis in patients with renal fibrosis. CONCLUSIONS: Collectively, our findings demonstrate that ATG5 modulates the inflammatory response by mediating pyroptosis and exacerbates UUO-induced renal fibrosis in endothelial cells, which is in striking contrast to its role in renal tubular epithelial cells. These results highlight the cell-type-specific functions of ATG5 during renal fibrogenesis. Furthermore, our study provides a novel theoretical basis for the development of targeted therapeutic strategies against renal fibrosis in clinical practice.
Trichomonas vaginalis-induced inflammation is associated with Th17 differentiation and tumor-intrinsic IL-17R signaling in prostate cancer progression.
Han IH, Sim S, Kim J … +2 more , Park SJ, Ryu JS
Inflamm Res · 2026 Jun · PMID 42371098 · Publisher ↗
OBJECTIVE: Chronic inflammation associated with infection has been implicated in prostate cancer (PCa) progression, yet the immunological mechanisms linking sexually transmitted pathogens to tumor development remain inco...
OBJECTIVE: Chronic inflammation associated with infection has been implicated in prostate cancer (PCa) progression, yet the immunological mechanisms linking sexually transmitted pathogens to tumor development remain incompletely understood. Trichomonas vaginalis (Tv), the most prevalent nonviral sexually transmitted parasite worldwide, has been associated with prostatic inflammation and increased PCa risk. However, how Tv-induced inflammation influences tumor progression has not been clearly defined. Here, we investigated whether Tv-induced epithelial inflammation promotes Th17 differentiation and drives prostate tumor progression through intratumoral IL-17 receptor (IL-17R) signaling. METHODS: Conditioned media of prostate epithelial cells (PECs, RWPE-1 cell line) was prepared by infection without (CM) and with Tv (TCM). Human CD4 T cells were isolated using the CD4 isolation kit from human peripheral blood. Conditioned medium of CD4 T cells was prepared by incubation with CM (T-CM) or TCM (T-TCM). RESULTS: Conditioned media from Tv-stimulated PECs induced robust production of IL-6 and IL-1β, which promoted IL-6/IL-1R-dependent differentiation of human CD4⁺ T cells into Th17 cells. Conditioned media from these Th17 cells enhanced proliferation and migration of prostate epithelial and cancer cells and activated IL-17R-TRAF6-NF-κB signaling pathways. Using a syngeneic mouse prostate cancer model in C57BL/6 mice, we found that IL-17R neutralization significantly reduced tumor growth without affecting Th17 cell abundance, supporting the involvement of tumor-intrinsic IL-17R signaling in Tvs-associated tumor progression. Spatial transcriptomic analysis further revealed enrichment of IL-17R-associated proliferative and invasive gene programs in Tvs-treated tumors. Consistently, analysis of prostate adenocarcinoma datasets showed that IL17RA expression was associated with proliferative and invasive signatures and poorer clinical outcomes. CONCLUSION: Collectively, these findings identify a Tv-Th17-IL-17R signaling axis linking infection-induced inflammation to tumor-intrinsic oncogenic signaling in prostate cancer, highlighting IL-17R signaling as a potential therapeutic target in inflammation-associated PCa.
Mechanism-centered target discovery across glomerulonephritis phenotypes: an integrative multi-omics study.
Liu J, Qiu X, Zeng D … +9 more , Li Y, Wang Y, Gu J, Kanwar YS, Chen L, Wei C, Wang Y, Wang W, Sun L
Inflamm Res · 2026 Jun · PMID 42371060 · Publisher ↗
BACKGROUND: Glomerulonephritis (GN) comprises a heterogeneous group of immune-mediated kidney disorders with substantial biological and clinical diversity. Current treatment still relies largely on broad immunosuppressio...
BACKGROUND: Glomerulonephritis (GN) comprises a heterogeneous group of immune-mediated kidney disorders with substantial biological and clinical diversity. Current treatment still relies largely on broad immunosuppression, underscoring the need for mechanism-informed target discovery across GN phenotypes. METHODS: We performed a program-guided integrative multi-omics study by combining cis-expression quantitative trait loci and cis-protein quantitative trait loci with GN genome-wide association datasets from UK Biobank, the GWAS Catalog, and FinnGen. Candidate genes were organized into four predefined mechanistic programs: cytokine/TNF signaling, cell-cycle/senescence-repair balance, complement/innate immune activation, and regulated cell-death/redox stress. Six GN-related outcomes were analyzed. Bayesian colocalization, cross-dataset meta-analysis, mouse knockout annotation, drug-repurposing assessment, network pharmacology, and rule-based evidence scoring were used to refine target prioritization. RESULTS: Integrative screening identified 42 transcriptomic and 12 proteomic putative targets, with the strongest enrichment in non-proliferative glomerulonephritis and primary membranoproliferative glomerulonephritis. Bayesian colocalization supported PPP2R1B in non-proliferative glomerulonephritis, SOD1 in IgA nephropathy, and CDK4 in primary membranoproliferative glomerulonephritis. Among 42 transcriptomic gene-outcome pairs taken forward, 11 were supported by cross-dataset meta-analysis. Proteomic meta-analysis supported several cross-dataset signals, including protective associations of ANXA5, GSR, and TNFRSF1B with glomerulonephritis. Across outcomes, complement/innate immunity and cytokine/TNF signaling formed the dominant shared backbone. After separating MHC-region signals for cautious interpretation, 31 non-MHC targets were retained for primary prioritization, with PPP2R1B, CDK4, and SOD1 comprising the top tier. CONCLUSIONS: This mechanism-centered integrative multi-omics study delineates shared and phenotype-enriched biological programs across the GN spectrum and identifies a prioritized set of candidate targets for future validation and therapeutic development.
Ethyl ferulate attenuates allergic asthma via inhibiting macrophage M2 polarization through STAT6/IRF4 pathway.
Ge L, Chen W, Han S … +8 more , Yang H, Du M, Li S, Bai X, Zhao P, Chen D, Pang Q, Wu Y
Inflamm Res · 2026 Jun · PMID 42371045 · Publisher ↗
OBJECTIVE: Allergic asthma is a chronic airway inflammatory disease with limited therapeutic options in clinical practice. Ethyl ferulate (EF), a natural compound commonly found in Chuanxiong, Danggui and grains, has bee...
OBJECTIVE: Allergic asthma is a chronic airway inflammatory disease with limited therapeutic options in clinical practice. Ethyl ferulate (EF), a natural compound commonly found in Chuanxiong, Danggui and grains, has been shown to possess multiple biological activities. However, the effect of EF on allergic asthma and its underlying mechanisms remains unclear. This study aimed to investigate the therapeutic potential and mechanism of EF in allergic asthma. METHODS: The house dust mite (HDM)-induced allergic asthma mouse model was used to evaluate the effects of EF on airway inflammation and macrophage M2 polarization. Adoptive transfer experiments were used to confirm the critical role of M2 polarization in the attenuation of allergic asthma by EF. Mechanistic studies were performed by using IL-4-stimulated RAW264.7 cells and bone marrow-derived macrophages (BMDMs). RESULTS: EF significantly attenuated HDM-induced airway inflammation, eosinophil infiltration, mucus secretion, and airway remodeling. EF suppressed M2 macrophage markers (CD206, Arg1, Ym1, Fizz1) in lung tissues and IL-4-stimulated macrophages. Mechanistically, EF blocked STAT6 phosphorylation and nuclear translocation, thereby inhibiting the STAT6/IRF4 pathway. CONCLUSIONS: EF alleviates allergic asthma by inhibiting M2 macrophage polarization via disruption of the STAT6/IRF4 signaling pathway, supporting its potential as a therapeutic agent derived from traditional medicine.
Re-evaluation of the prognosis of patients with IgA nephropathy and mild proteinuria: a longitudinal study with unexpected results.
Ma X, Zhang S, Chen W … +1 more , Zhou X
Inflamm Res · 2026 Jun · PMID 42371044 · Full text
BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a major cause of chronic kidney disease. Mild proteinuria (< 0.5 g/24 h) is generally considered to indicate a favorable prog...
BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a major cause of chronic kidney disease. Mild proteinuria (< 0.5 g/24 h) is generally considered to indicate a favorable prognosis in IgAN. This study aimed to explore the clinicopathological features and prognostic factors of such patients. METHOD: We performed a retrospective analysis of IgAN patients who had renal biopsies at our hospital from 2008 to 2023. We included patients with 24-hour proteinuria < 0.5 g, age ≥ 15 years, and follow-up ≥ 12 months. Risk factors were assessed using logistic regression and Cox proportional hazards models. RESULTS: Over a mean follow-up of 90.75months, 27 patients(10.19%) experienced endpoint events. The overall eGFR slope was - 2.07mL/min/1.73 m per year. Greater eGFR decline correlated with lower 10-year renal survival. Multivariate analysis showed severe tubulointerstitial damage, lower baseline eGFR and steeper eGFR decline were independent risk factors for renal endpoint events. Renal arteriolar lesions, lower baseline eGFR, steeper eGFR decline, and lower TyG-BMI were risk factors for poor renal prognosis. CONCLUSIONS: Our study challenges the assumption that IgAN patients with mild proteinuria have a favorable prognosis. Over 90.75 months, 10.19% of patients experienced endpoint events, with an eGFR decline of 2.07 mL/min/1.73 m per year. These findings indicate significant disease progression risk in IgAN patients with mild proteinuria. In addition to traditional risk factors, metabolic factors such as TyG-BMI are important prognostic predictors.
Reconceptualizing chorioamnionitis as an immune-mediated inflammatory disorder at the maternal-fetal interface.
Wang TM, Shen CM, Lin SC … +3 more , Hsieh WS, Hung YL, Guo JW
Inflamm Res · 2026 Jun · PMID 42350648 · Full text
BACKGROUND: Chorioamnionitis has long been regarded as an infection-driven obstetric disorder, yet converging clinical, pathological, and mechanistic evidence demonstrates that host-derived inflammatory pathways, togethe...
BACKGROUND: Chorioamnionitis has long been regarded as an infection-driven obstetric disorder, yet converging clinical, pathological, and mechanistic evidence demonstrates that host-derived inflammatory pathways, together with microbial factors, critically shape placental injury, fetal involvement, and neonatal outcomes. Histological inflammation of the chorioamniotic membranes correlates more strongly with adverse outcomes than microbial detection alone, underscoring the importance of host immune responses even in the context of microbial invasion. PURPOSE: This review aims to synthesize current insights into the immune landscape of the maternal-fetal interface, the coordinated contributions of multiple immune pathways, the interplay between microbial and non-microbial triggers, and the downstream consequences for fetal and neonatal health. Rather than replacing the infection-based paradigm, we aim to extend it by integrating immunological mechanisms that account for disease heterogeneity and variable clinical outcomes. METHODS: A narrative review was conducted using a structured literature identification strategy. Relevant peer-reviewed original studies, review articles, clinical investigations, and translational studies were identified through targeted literature searches and synthesized according to their mechanistic and clinical relevance. RESULTS: Sterile intra-amniotic inflammation can produce overlapping responses with infection, arising from partially distinct mechanisms and representing a context-dependent extension within infection-associated processes, without constituting a separate primary pathway. Advances in maternal-fetal immunology identify the maternal-fetal interface as a dynamic immune environment in which disrupted tolerance, heightened pattern-recognition signaling, and amplified cytokine and chemokine networks lower the threshold for pathological activation. Multiple pathways including interleukin-1 and interleukin-6 signaling, macrophage activation, and neutrophil-mediated responses collectively drive this process. In this context, neutrophil extracellular traps formation represents an important effector mechanism linking microbial and non-microbial cues to tissue-destructive inflammation. Fetal exposure to these pathways results in immune programming consistent with the fetal inflammatory response syndrome, contributing to pulmonary, intestinal, and neurodevelopmental sequelae. Although antibiotics remain essential for infection control, they do not directly target downstream immune circuits sustaining placental inflammation or fetal injury. CONCLUSIONS: Reframing chorioamnionitis as an immune-mediated disorder, while preserving the central role of infection, supports endotype-based classification and targeted immunomodulation. It also highlights the potential of microbiota-informed strategies beyond pathogen eradication, with implications for preventing preterm birth and improving neonatal outcomes.
Endoglin is not a mediator in 7-ketocholesterol-induced endothelial activation in liver sinusoidal endothelial cells in vitro.
Fikrova P, Tripska K, Eissazadeh S … +8 more , Vasinova M, Diepoltova A, Rathouska JU, Nemeckova I, Havelek R, Mohammadi S, Igreja Sa IC, Nachtigal P
Inflamm Res · 2026 Jun · PMID 42329430 · Full text
BACKGROUND: Endoglin (ENG) is expressed in liver sinusoidal endothelial cells (LSECs), where it regulates endothelial activation and inflammation. The 7-ketocholesterol (7-K), a cholesterol oxidation product, accumulates...
BACKGROUND: Endoglin (ENG) is expressed in liver sinusoidal endothelial cells (LSECs), where it regulates endothelial activation and inflammation. The 7-ketocholesterol (7-K), a cholesterol oxidation product, accumulates in the liver and induces endothelial dysfunction. ENG has been shown to play an important role in adhesion processes in other endothelial models but its role in LSECs upon 7-K exposure remains unclear. We hypothesized that 7-K treatment of LSECs would confirm the critical role of ENG in endothelial activation, potentially outweighing the contributions of the cell adhesion molecules VCAM-1 and ICAM-1. METHODS: Human LSECs were exposed to 25 µM 7-K. Protein expression and monocyte adhesion were assessed by flow cytometry, and soluble ENG was measured by ELISA. RESULTS: 7-K reduced ENG expression, while ICAM-1 was markedly upregulated. 7-K increased monocyte adhesion to LSECs, which was abrogated by ICAM-1, but not by ENG neutralization. CONCLUSION: We showed that 7-K promotes a pro-inflammatory phenotype defined by ICAM-1, rather than ENG. Thus, we propose that individual roles of ENG, ICAM-1, and VCAM-1 must be carefully considered when studying endothelial dysfunction.
Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K-NF-κB pathway drives M1 macrophage polarization in renal ischemia-reperfusion injury.
Wang H, Sun J, Li X … +6 more , Ma H, Luo Y, Qin M, Zhang H, Bian H, Li J
Inflamm Res · 2026 Jun · PMID 42329408 · Publisher ↗
BACKGROUND: Ferroptosis and macrophage activation are key contributors to the development of acute kidney injury (AKI). Ferroptosis is accompanied by metabolic reprogramming and the release of soluble mediators, includin...
BACKGROUND: Ferroptosis and macrophage activation are key contributors to the development of acute kidney injury (AKI). Ferroptosis is accompanied by metabolic reprogramming and the release of soluble mediators, including metabolites, cytokines, and extracellular signals, which can propagate tissue damage and modulate immune responses. However, the metabolic profile of ferroptotic tubular epithelial cells and its impact on the immune microenvironment during ischemia-reperfusion injury (IRI) remains largely unexplored. METHODS: Using untargeted metabolomics, we found that ferroptotic cells secreted abnormally elevated levels of methylmalonic acid (MMA), and investigated the physiological role of MMA in acute kidney injury in mice. Furthermore, through transcriptomics and Western blotting, we explored the mechanism by which the ferroptosis-associated metabolite MMA promotes macrophage polarization. RESULTS: Here, untargeted metabolomics revealed a distinct metabolic secretome of ferroptotic tubular epithelial cells, with the level of MMA markedly elevated after IRI. Mechanistic studies demonstrated that MMA activated the PI3K/ Akt /NF-κB pathway in macrophages, driving M1 polarization and increasing the secretion of proinflammatory cytokines such as IL-6 and TNF-α, ultimately exacerbating acute kidney injury. CONCLUSION: These findings reveal the mechanism of metabolite-immune crosstalk in AKI, and suggest that targeting the ferroptosis-macrophage axis may represent a therapeutic strategy to disrupt the vicious cycle of inflammation and tissue injury.
Defective efferocytosis in diabetes: molecular mechanisms and emerging therapeutic strategies.
Lei Y, Tang M, Deng H … +8 more , Li Y, Wu J, Luo L, Mou Y, Wu Q, Li Q, Xu Y, Huang W
Inflamm Res · 2026 Jun · PMID 42329402 · Publisher ↗
BACKGROUND: Diabetes is associated with oxidative stress, systemic immune dysregulation and chronic low-grade inflammation, which contributes to a wide spectrum of microvascular and macrovascular complications. Efferocyt...
BACKGROUND: Diabetes is associated with oxidative stress, systemic immune dysregulation and chronic low-grade inflammation, which contributes to a wide spectrum of microvascular and macrovascular complications. Efferocytosis, the phagocytic clearance of apoptotic cells by macrophages and dendritic cells, is essential for inflammation resolution and tissue repair. Defective efferocytosis has been increasingly implicated in the progression of diabetes and several of its major complications, including atherosclerosis, nephropathy, retinopathy, impaired wound healing, and osteoporosis. OBJECTIVES: This narrative review is prepared through a focused literature search of studies investigating efferocytosis in diabetes, elucidates how its disruption contributes to the progression of diabetic complications, and further highlight emerging therapeutic strategies aimed at regulating efferocytosis. This paper is expected to provide direction and outlook for the research on efferocytosis and diabetes. RESULTS: Efferocytosis regulation involves a coordinated cascade of find-me signals, engulfment receptors, intracellular cytoskeletal remodeling, and metabolic reprogramming. This review summarizes the key molecular changes of defective efferocytosis and pathological changes in diabetic complications. Importantly, emerging preclinical studies have demonstrated that restoring efferocytosis ameliorate inflammation, promote tissue regeneration, and interrupt the progression of diabetic complications. CONCLUSIONS: Efferocytosis not only illuminates fundamental aspects of immune regulation but also opens up new therapeutic possibilities. As the field continues to evolve, integrating efferocytosis-based interventions into the broader therapeutic landscape of diabetes may represent a paradigm shift in the management of its chronic complications.
Extracellular vesicle-mediated mechanisms and therapeutic potential in acute lung injury.
Song Y, Zhang X, Wang D … +2 more , Li Z, Li Y
Inflamm Res · 2026 Jun · PMID 42323526 · Publisher ↗
BACKGROUND: Acute lung injury (ALI) is a severe inflammatory lung disorder characterized by disruption of the alveolar-capillary barrier and impaired gas exchange, often progressing to acute respiratory distress syndrome...
BACKGROUND: Acute lung injury (ALI) is a severe inflammatory lung disorder characterized by disruption of the alveolar-capillary barrier and impaired gas exchange, often progressing to acute respiratory distress syndrome and respiratory failure. Current treatments are largely supportive with limited efficacy, underscoring the need for novel therapeutic strategies. PURPOSE: This review summarizes current evidence on extracellular vesicles (EVs) in ALI and evaluates their potential as therapeutic agents and biomarkers. METHODS: A comprehensive literature review was conducted focusing on the biological functions, mechanisms of action, and translational potential of EVs in ALI. RESULTS: EVs are key mediators of intercellular communication in ALI. They exert anti-inflammatory, antioxidant, and pro-regenerative effects through transfer of bioactive cargo, thereby modulating immune responses, preserving endothelial and epithelial barrier integrity, and promoting tissue repair. EVs derived from mesenchymal stem cells and endothelial progenitor cells demonstrate protective effects against lung injury and vascular dysfunction in preclinical studies. In addition, EVs hold promise as natural drug delivery systems due to their low immunogenicity and ability to cross biological barriers, as well as potential biomarkers for ALI. CONCLUSION: EVs represent a promising cell-free therapeutic platform for ALI, with applications in immunomodulation, tissue repair, drug delivery, and diagnosis. However, further mechanistic studies and rigorous translational validation are required to support clinical application.
Lactylation: a novel post-translational modification for cGAS-STING pathway.
Wang H, Wang Z, Meng F … +6 more , Gao Y, Zhang M, Zhang W, Wang E, Shi K, Jin Y
Inflamm Res · 2026 Jun · PMID 42323525 · Publisher ↗
BACKGROUND: Lysine lactylation (Kla) is a lactate-derived post-translational modification that has emerged as a critical metabolic-epigenetic regulator linking cellular metabolic states to innate immune signaling. The cG...
BACKGROUND: Lysine lactylation (Kla) is a lactate-derived post-translational modification that has emerged as a critical metabolic-epigenetic regulator linking cellular metabolic states to innate immune signaling. The cGAS-STING pathway, a central cytosolic DNA-sensing mechanism essential for antiviral defense, antitumor immunity, and inflammatory regulation, is profoundly influenced by the metabolic milieu. However, the precise role of lactylation in modulating this pathway remains to be systematically synthesized. OBJECTIVE: This review aims to comprehensively analyze the molecular mechanisms by which lysine lactylation regulates the cGAS-STING signaling axis, and to discuss the pathophysiological implications and therapeutic potential of targeting this modification in diseases ranging from autoimmunity and neuroinflammation to cancer. METHODS: A comprehensive review of the relevant literature was conducted to summarize the biochemical basis of lactylation (including writers, erasers, and readers) and to systematically examine emerging evidence demonstrating direct and indirect regulation of cGAS-STING components by lactylation. Studies involving site-specific modifications, disease models, and therapeutic interventions were collated and analyzed. RESULTS: Lactylation directly targets core pathway components-cGAS at residues such as K21, K131, K156, K162, K275, and K409, and STING-altering their stability, enzymatic activity, DNA-binding capacity, phase separation, and downstream signaling outputs. Depending on context, lactylation exerts dual effects: it stabilizes cGAS and amplifies type I interferon responses in autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis) and hypoxic-ischemic encephalopathy, but promotes cGAS degradation or suppresses STING activity in cancer (lung adenocarcinoma, glioblastoma) and neuropathic pain, thereby facilitating immune evasion or pain sensitization. Indirectly, lactylation modulates cytosolic DNA ligand availability by influencing mitochondrial DNA release (via HMGB1, VDAC1, Arg1, DRP1) or DNA repair (via KU70). The discovery of specific lactyltransferases (AARS1/2, p300) and delactylases (SIRT1-3, HDAC1-3) establishes lactylation as a dynamic, enzymatically controlled process. CONCLUSION: Lactylation functions as a pivotal metabolic-immune checkpoint that fine-tunes cGAS-STING signaling in a cell-type- and disease-specific manner. Targeting the lactylation regulatory axis-by inhibiting pathogenic lactylation to restore anti-tumor immunity or enhancing it to dampen deleterious inflammation-offers a novel immunometabolic therapeutic strategy for autoimmune disorders, chronic infections, neurodegeneration, and cancer.
Transcriptomics and metabolomics reveal the protective effect of β-hydroxybutyrate on sepsis associated encephalopathy.
Liang JW, Chen Y, Liu CY … +4 more , Zeng YF, Sun ZD, Liang MH, He HF
Inflamm Res · 2026 Jun · PMID 42323517 · Publisher ↗
BACKGROUND: In this study, metabolomics and transcriptomics were applied to reveal the potential mechanisms underlying the protective effects of β-hydroxybutyrate (BHB) on sepsis-associated encephalopathy (SAE). METHODS:...
BACKGROUND: In this study, metabolomics and transcriptomics were applied to reveal the potential mechanisms underlying the protective effects of β-hydroxybutyrate (BHB) on sepsis-associated encephalopathy (SAE). METHODS: A mouse SAE model was established. The Barnes maze was used to evaluate cecal ligation and puncture (CLP)-induced cognitive impairment. Neuronal survival, microglial activation, and proinflammatory cytokine levels were assessed using Nissl staining, immunofluorescence staining, and RT-qPCR. Serum metabolites and cerebral genes from control, SAE, and SAE mice treated with BHB were compared. Metabolomics and transcriptomics analysis were performed. Finally, based on the integrated transcriptomic and metabolomic analyses, we identified the target signaling pathway. RESULTS: Our results demonstrated that β-hydroxybutyrate (BHB) markedly reversed CLP-induced cognitive impairment. BHB administration attenuated neuronal loss and histopathological damage in the hippocampus, accompanied by reduced production of pro-inflammatory cytokines and decreased activation of Iba-1-positive microglia in SAE mice. Metabolomic profiling revealed that SAE induced significant alterations in serum metabolic signatures, with galactose, glycerophosphocholine, taurine, and hypotaurine levels markedly decreased. BHB treatment partially restored these metabolite levels toward normal. Transcriptomic analysis identified significant enrichment of the NF-κB signaling pathway in response to BHB treatment in SAE mice. Correlation analysis further showed that NF-κB-associated inflammatory genes (including VCAM1, TNF, NFKBIA, NFKB1, IL6, IL1B, ICAM1, CXCL family members, CD40, and CCL4/5) were strongly and negatively correlated with galactose, hypotaurine, and taurine levels, whereas glycerophosphocholine exhibited weak or non-significant associations. Consistent with the multi-omics findings, protein-level validation by Western blot confirmed that BHB suppressed SAE-induced activation of the NF-κB pathway in hippocampal tissue. CONCLUSION: Overall, this study reveals that BHB exerts neuroprotective effects in SAE through integrated metabolic and transcriptional reprogramming, in which attenuation of NF-κB-mediated inflammatory signaling represents a key mechanistic link between altered serum metabolites and downstream gene expression changes.
WNT4 reprograms dental pulp stem cells to resist PANoptosis and rebuild neurogenic potential for facial nerve injury repair.
Xu W, Xi H, Lin S … +7 more , Yao L, Sun J, Xue B, Piao G, Liu Y, Sun W, Wang X
Inflamm Res · 2026 Jun · PMID 42323514 · Full text
OBJECTIVE AND DESIGN: This study investigated the protective role and molecular mechanism of WNT4 in preserving the viability and neurogenic potential of dental pulp stem cells (DPSCs) within an inflammatory microenviron...
OBJECTIVE AND DESIGN: This study investigated the protective role and molecular mechanism of WNT4 in preserving the viability and neurogenic potential of dental pulp stem cells (DPSCs) within an inflammatory microenvironment following facial nerve injury (FNI). MATERIAL OR SUBJECTS: Human DPSCs (hDPSCs; authenticated by surface marker profiling and multi-lineage differentiation) and a rat model of facial nerve transection (n = 15 per group) were utilized. TREATMENT: In vitro, hDPSCs were treated with TNF-α(10 ng/mL) to model inflammation. In vivo, WNT4-overexpressing or control DPSCs (1 × 10 cells) were injected into the tail vein immediately after nerve transection. METHODS: PANoptosis and neurogenic differentiation were assessed by Western blot, flow cytometry, and immunofluorescence staining. Transcriptional regulation was analyzed by dual-luciferase reporter assay and ChIP-qPCR. Protein interaction was examined by LC-MS/MS and docking. In vivo recovery was monitored by functional assessments and histology. RESULTS: WNT4 overexpression significantly attenuated TNF-α-induced PANoptosis in hDPSCs and restored their neurogenic potential. Mechanistically, KLF7 transcriptionally activated WNT4. WNT4 interacted with NOTCH1, activating Wnt/β-catenin signaling and upregulating c-Jun, CYCD1, and VEGFA. In vivo, engineered hDPSCs reduced local inflammation and accelerated functional recovery and histological repair. CONCLUSIONS: WNT4 protects DPSCs against inflammatory PANoptosis and enhances neuroreparative potential, providing a basis for optimizing stem cell therapy in FNI.
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