Molecular Immunology[JOURNAL]
Sun
200 papers
Neutrophil elastase-SERPINB1 axis in epithelial responses: Cell death, inflammation and SERPINB1 dynamics.
Kilic B, Akel Bilgic H, Karaaslan C
Mol Immunol · 2026 Jul · PMID 42400974 · Publisher ↗
Chronic inflammatory lung diseases are associated with elevated levels of neutrophil elastase (NE), leading to epithelial damage and dysregulated cellular responses. However, the molecular mechanisms underlying NE-mediat...
Chronic inflammatory lung diseases are associated with elevated levels of neutrophil elastase (NE), leading to epithelial damage and dysregulated cellular responses. However, the molecular mechanisms underlying NE-mediated disruption of epithelial anti-protease defenses, including the regulation of SERPINB1, remain poorly defined. In this study, we investigated NE-induced responses in bronchial epithelial cells cultured at air-liquid interface (ALI) focusing on epithelial cell death, inflammation, and SERPINB1 dynamics. NE exposure induced dose- and time-dependent cytotoxicity, accompanied by morphological alterations, mitochondrial membrane depolarization, and modest changes in caspase-3, -8, and -9 activity. In ALI cultures, NE was applied either apically, basolaterally or to both compartments simultaneously to evaluate exposure-side-dependent epithelial responses. NE differentially modulated apoptosis-related gene expression, including changes in BCL2, BAX, CASP3, CASP8, CASP9, PARP1, and AIF, depending on NE concentration and exposure side. Cytokine profiling revealed dose-, exposure-side-, and sampling-compartment-dependent changes in IL-6, IL-8, and GM-CSF secretion. Importantly, SERPINB1 expression was markedly reduced at both mRNA and protein levels, while domain-specific immunofluorescence suggested altered SERPINB1 localization and epitope accessibility, suggesting functional alterations beyond transcriptional loss. siRNA-mediated SERPINB1 knockdown further modified NE-associated apoptosis-related gene expression, supporting a functional link between NE exposure and epithelial SERPINB1 regulation. Collectively, these findings establish the NE-SERPINB1 axis as a critical determinant of epithelial cell fate, contributing to epithelial apoptosis, inflammatory mediator release, and protease-antiprotease imbalance. This study provides a systematic analysis of dose- and exposure-side-dependent epithelial responses to NE under ALI culture conditions. Our results highlight the NE-SERPINB1 axis as a contributor to epithelial dysfunction in chronic airway inflammation and support the exploration of SERPINB1-modulating strategies for preserving epithelial integrity and mitigating neutrophil-driven pathology in lung diseases.
Phillyrin alleviates pulmonary fibrosis via modulation of the TGF-β1/Smad and Nrf2/HO-1 signaling pathways.
Liu Y, Liu L, Song H … +9 more , Ma Y, Luo Y, Wen S, Li L, Xia S, Zhu R, Zhang D, Li W, Niu X
Mol Immunol · 2026 Jul · PMID 42400973 · Publisher ↗
PURPOSE: Pulmonary fibrosis (PF) is a fatal disease with limited treatment options. This study aimed to investigate the therapeutic potential of phillyrin (Phi), a bioactive compound derived from Forsythia suspensa, in t...
PURPOSE: Pulmonary fibrosis (PF) is a fatal disease with limited treatment options. This study aimed to investigate the therapeutic potential of phillyrin (Phi), a bioactive compound derived from Forsythia suspensa, in treating PF and to explore its underlying mechanisms. METHODS: A bleomycin (BLM)-induced murine PF model and TGF-β1-stimulated L929 fibroblasts were employed. Histopathological changes, collagen deposition, inflammatory cytokines (IL-1β, TNF-α), oxidative stress markers (MDA, SOD, GSH), and fibrotic proteins (α-SMA, COL1A1, etc.) were evaluated. Key signaling pathways, including Nrf2/HO-1 and TGF-β1/Smad2/3, were analyzed. RESULTS: Phi significantly attenuated BLM-induced lung damage, collagen accumulation, and fibrosis scores (p < 0.001). It suppressed inflammation and oxidative stress by activating the Nrf2/HO-1 pathway. In TGF-β1-stimulated L929 cells, Phi inhibited proliferation, migration, invasion, and extracellular matrix (ECM) deposition. Furthermore, Phi attenuated TGF-β1-induced G2/M phase cell cycle arrest and reduced the levels of key fibrotic proteins. These effects were mediated through suppression of the TGF-β1/Smad2/3 pathway and epithelial-mesenchymal transition (EMT). CONCLUSION: Phi exerts anti-fibrotic, antioxidant, and anti-inflammatory effects by dual modulation of the TGF-β1/Smad2/3 and Nrf2 pathways, demonstrating significant therapeutic potential for pulmonary fibrosis. It is noteworthy that the in vitro evidence comes from L929 fibroblasts, and further validation in lung-relevant cell models would strengthen the translational relevance of these findings.
m6A modification of LINC00458 enhances HMOX1 stability via ELAVL1 recruitment to promote ferroptosis and aggravate asthma.
Yu X, Chen L, Liang J … +6 more , He Z, Xu J, Huang Z, Liang H, Lu C, Zhai Y
Mol Immunol · 2026 Jun · PMID 42361514 · Publisher ↗
BACKGROUND: Asthma is a chronic inflammatory disease of the airways, characterized by immune cell infiltration and airway hyperresponsiveness. Recent studies have identified lncRNAs as key regulators in asthma pathogenes...
BACKGROUND: Asthma is a chronic inflammatory disease of the airways, characterized by immune cell infiltration and airway hyperresponsiveness. Recent studies have identified lncRNAs as key regulators in asthma pathogenesis, but the underlying mechanisms remain unclear. LINC00458, a lncRNA, has been implicated in various diseases, yet its role in asthma has not been thoroughly investigated. AIM: This study aims to explore the role of LINC00458 in asthma and its potential mechanism in regulating inflammation and ferroptosis. METHODS: The expression of LINC00458 in asthma cells and tissues was measured using qPCR. The effects of LINC00458 knockdown were evaluated in primary human bronchial epithelial (NHBE) cells treated with house dust mite (HDM) extract. The interaction between LINC00458 and ELAVL1 was assessed using RNA pulldown and RIP-qPCR. HMOX1 mRNA stability and its impact on ferroptosis were also analyzed. Finally, the m6A modification of LINC00458 was examined using MeRIP-qPCR and RNA pulldown assays. RESULTS: LINC00458 was upregulated in asthma cells and tissues. Knockdown of LINC00458 suppressed ferroptosis and inflammatory cytokine release. LINC00458 stabilized HMOX1 mRNA by interacting with the RNA-binding protein ELAVL1. Furthermore, METTL3-mediated m6A modification promoted the stability of LINC00458, enhancing its inflammatory response regulation. CONCLUSION: LINC00458 plays a significant role in asthma by modulating inflammation and ferroptosis. Its interaction with ELAVL1 and m6A modification pathway suggests potential therapeutic targets for asthma treatment.
Overexpression of Hes1 inhibits cigarette smoke-induced mitochondrial apoptosis in AT2 cells by activating the Pgc-1α/Tfam signaling pathway.
Yan L, Zhang X, Shao P … +4 more , Li M, Huang Q, Xu W, Wu J
Mol Immunol · 2026 Jun · PMID 42361513 · Publisher ↗
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. Apoptosis of alveolar type 2 (AT2) cells contributes to COPD progression, and understanding its mechanisms may reveal ne...
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. Apoptosis of alveolar type 2 (AT2) cells contributes to COPD progression, and understanding its mechanisms may reveal new therapies. METHODS: Bioinformatics analysis of GSE69818 and GSE76925 datasets showed that Hes1 was associated with COPD severity and positively correlated with PPARGC1A. We then established mouse and cell models with AT2 cell‑specific Hes1 overexpression and exposed them to cigarette smoke (CS) or extract (CSE). Pathological changes (H&E, Masson), apoptosis (TUNEL, Western blot), mitochondrial ultrastructure (electron microscopy), oxidative stress (DHE), and downstream protein levels were assessed. Finally, CUT&Tag sequencing and qPCR were performed to verify Hes1 binding sites in the PPARGC1A promoter, and a Pgc‑1α inhibitor (SR‑18292) was used to test the functional requirement of Pgc‑1α in Hes1‑mediated protection. RESULTS: After 12 weeks of CS exposure, Hes1 overexpression reduced alveolar destruction, apoptosis, inflammation, and oxidative stress. It also increased mitochondrial number and restored cristae structure in AT2 cells. In MLE-12 and A549 cells, Hes1 overexpression similarly reduced CSE‑induced apoptosis and improved mitochondrial recovery. Furthermore, Hes1 overexpression elevated Pgc‑1α and Tfam protein levels both in vivo and in vitro. Importantly, inhibition of Pgc‑1α by SR‑18292 partially reversed the anti‑apoptotic effect of Hes1, confirming that Pgc‑1α is essential for Hes1‑mediated protection. CONCLUSION: These findings indicate that Hes1 overexpression activates the Pgc‑1α/Tfam pathway, thereby inhibiting CS‑induced mitochondrial apoptosis in AT2 cells. Targeting Hes1 may represent a promising COPD treatment.
Progesterone promotes favorable pregnancy outcomes in recurrent spontaneous, abortion by attenuating NK Cell overactivation and upregulating the cAMP/PKA/CREB signaling axis.
Dai Q, Deng X, Wan L … +2 more , Wu X, Zuo L
Mol Immunol · 2026 Jun · PMID 42335669 · Publisher ↗
OBJECTIVE: Recurrent spontaneous abortion (RSA) is a common pregnancy complication with complex etiology, in which immune dysregulation is critical. Although progesterone (P4) is widely used clinically for RSA, its mecha...
OBJECTIVE: Recurrent spontaneous abortion (RSA) is a common pregnancy complication with complex etiology, in which immune dysregulation is critical. Although progesterone (P4) is widely used clinically for RSA, its mechanism in regulating NK cell function remains unclear. METHODS: We analyzed decidual tissues from patients with RSA and from healthy gestational controls, and established a rat model of RSA treated with graded P4. Histopathological analysis, RT-qPCR, Western blotting, RNA sequencing (RNA-Seq), and flow cytometry were employed to evaluate cytokine profiles, the proportion of CD3CD161 NK cells, candidate gene expression, and activation of the cAMP/PKA/CREB signaling pathway. RESULTS: In patients with RSA and in the RSA rat model, IFN-γ and TNF-α levels were elevated, whereas VEGF levels were decreased-accompanied by an increased proportion of CD3⁻CD161⁺ NK cells. P4 treatment significantly reduced the embryo loss rate, improved the morphological structure of the decidua tissue, and effectively inhibited the expression of inflammatory cytokines and the excessive activation of CD3⁻CD161⁺NK cells. Transcriptomic analysis identified the cAMP signaling pathway as a key dysregulated pathway; cAMP/PKA/CREB signaling was suppressed in RSA but restored by P4. Mx1 was upregulated in RSA and reversed by P4, showing negative correlations with PKA/CREB activation and positive correlations with pro-inflammatory cytokines. CONCLUSION: P4 improves the pregnancy outcome of RSA by inhibiting the excessive activation of CD3⁻CD161⁺NK cells and activating the cAMP/PKA/CREB signaling pathway; Mx1 may play a negative regulatory role in this pathway.
Oleanolic acid alleviates hepatic fibrosis by inhibiting liver macrophage recruitment and polarization.
Jia W, Shi T, Qin M … +8 more , Wang Y, Jiang W, Tan S, Sun H, Wan R, Zhang Z, He S, Sun H
Mol Immunol · 2026 Jun · PMID 42335668 · Publisher ↗
BACKGROUND: Liver fibrosis is a key pathological step in chronic liver disease progression, yet effective therapies are scarce. Oleanolic acid (OA) exhibits hepatoprotective effects, but whether it ameliorates fibrosis b...
BACKGROUND: Liver fibrosis is a key pathological step in chronic liver disease progression, yet effective therapies are scarce. Oleanolic acid (OA) exhibits hepatoprotective effects, but whether it ameliorates fibrosis by regulating macrophages is unknown. This study hypothesized that OA attenuates liver fibrosis by suppressing macrophage recruitment and polarization. METHODS: A CCl-induced mouse fibrosis model was established with or without macrophage depletion. Hepatic pathology, liver function, and fibrosis markers were assessed. Macrophage markers and M1/M2 subsets were analyzed. Macrophage-stellate cell crosstalk was studied via conditioned medium co-culture. Transcriptome sequencing and r-FosB rescue experiments identified the underlying mechanism. RESULTS: OA dose-dependently alleviated CCl₄-induced liver fibrosis in mice, reducing serum markers of liver injury, fibrosis, and inflammation, as well as downregulating TGF-β and FN1 expression. OA significantly suppressed macrophage recruitment and decreased M1/M2 proportions and marker expression, with no significant cytotoxicity to macrophages at the tested concentrations. Macrophage depletion markedly attenuated OA's anti-fibrotic effects. In vitro, OA directly inhibited M1/M2 polarization and indirectly suppressed LX-2 cell activation via paracrine regulation. Transcriptomics identified FosB as a key downregulated gene; recombinant r-FosB reversed OA's inhibitory effects on macrophage polarization and stellate cell activation. CONCLUSION: OA alleviates liver fibrosis by inhibiting FosB/ΔFosB-mediated macrophage recruitment and polarization imbalance, thereby regulating macrophage-stellate cell interactions. This study provides novel evidence for its clinical application.
Cordycepin attenuates diabetic nephropathy by dual-pathway activation of TFEB to restore autophagy and ameliorate podocyte injury.
Li J, Chen S, Suo J … +9 more , Ma Y, Lu Z, Cai S, Chen H, Chen Z, Deng Z, Tang C, Zhang Q, Ma B
Mol Immunol · 2026 Jun · PMID 42322973 · Publisher ↗
Currently, effective therapeutic strategies to halt the irreversible decline of renal function in diabetic nephropathy (DN) are limited. This study aimed to investigate the renoprotective effects of Cordycepin (COR), a b...
Currently, effective therapeutic strategies to halt the irreversible decline of renal function in diabetic nephropathy (DN) are limited. This study aimed to investigate the renoprotective effects of Cordycepin (COR), a bioactive adenosine analog derived from Cordyceps militaris, in a mouse model of DN and to elucidate its underlying mechanisms. In a type II diabetic mouse model induced by a high-fat diet and streptozotocin, COR treatment attenuated hyperglycemia and renal dysfunction, ameliorated glomerular injury, and restored the expression of Nephrin, a critical slit-diaphragm protein in podocytes. In vitro, in palmitic acid (PA)-induced podocyte injury, COR treatment elevated cell viability and upregulated Nephrin expression dose-dependently. Mechanistically, COR restored impaired autophagic flux under diabetic conditions by improving autophagosome maturation, autophagosome-lysosome fusion, and lysosomal degradation, as demonstrated by the normalized profile of autophagy markers (LC3-II/I, p62, Beclin-1, LAMP1). This pro-autophagic activity was essential for its protection, which was abolished by 3-MA and enhanced by rapamycin. Subsequently, we identified transcription factor EB (TFEB) as the central mediator of COR's action. COR dually regulates TFEB through two synchronized pathways: it inhibits the mTORC1 axis to promote TFEB nuclear translocation and transcriptional activity, while simultaneously suppressing K48-linked polyubiquitination to prevent its proteasomal degradation, and enhancing its stability. TFEB was essential for restoring autophagic flux and podocyte integrity, with overexpression reversing and knockdown exacerbating PA‑induced injury. In summary, our findings demonstrate that COR alleviates DN by coordinately enhancing the activity and stability of TFEB. This work reveals a novel dual-targeting mechanism and proposes a promising therapeutic strategy for diabetic nephropathy.
Endothelial-derived TWEAK drives granulosa cell apoptosis in PCOS via the Fn14-oxidative stress axis.
Chen F, Gu T, Wu J
Mol Immunol · 2026 Jun · PMID 42296934 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, characterized by aberrant follicular development and a dysregulated ovarian microenvironment. The roles of in...
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, characterized by aberrant follicular development and a dysregulated ovarian microenvironment. The roles of intercellular communication, particularly between ovarian endothelial cells and granulosa cells, remain poorly understood. The TWEAK (TNF-like weak inducer of apoptosis)-Fn14 (fibroblast growth factor-inducible 14) axis, implicated in apoptosis and cellular stress, represents a potential but unexplored pathway in PCOS. METHODS: A mouse single-cell RNA-seq dataset (GSE268919) was analyzed to define cell-type composition and ligand-receptor pair in PCOS. To investigate the alterations in endothelial cells and granulosa cells in PCOS, a dehydroepiandrosterone (DHEA)-induced PCOS mouse model was established for histology, Enzyme-Linked Immunosorbent Assay (ELISA), and immunofluorescence (IF). Preliminary mechanism studies were performed using bioinformatics analysis and in vitro endothelial-supernatant culture of granulosa cells. RESULTS: Single-cell analysis revealed altered proportions and transcriptomes of endothelial and granulosa cells in PCOS. The PCOS mouse model confirmed estrus cycle disruption, endocrine dysfunction, aberrant ovarian angiogenesis, and granulosa cell apoptosis. Cell communication predicted a novel endothelial-granulosa cell communication in PCOS via the TWEAK-Fn14 ligand-receptor pair. Furthermore, TWEAK was upregulated in ovarian endothelial cells, while Fn14 was elevated in granulosa cells. Functionally, endothelial-derived TWEAK promoted oxidative-stress responses and apoptosis in granulosa cells by upregulating Fn14 expression, at least in part. CONCLUSION: Endothelial-derived TWEAK drives a TWEAK-Fn14 axis-mediated intercellular communication that promotes oxidative-stress responses and apoptosis in granulosa cells in PCOS. Targeting this endothelial-granulosa signaling pathway may offer a novel therapeutic strategy to preserve follicular integrity in PCOS.
Transcription factor ID3 promotes fibroblast differentiation and proliferation in lung fibrosis through augmenting the TGF-β signaling pathway.
Li F, Geng W, Li G … +8 more , Ning W, Wang S, Abdulkadir AA, Yang G, Li F, Du H, Xiao Y, Su X
Mol Immunol · 2026 Jun · PMID 42296933 · Publisher ↗
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by myofibroblast activation, accumulation, and excessive extracellular matrix deposition. Although fibroblast activati...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by myofibroblast activation, accumulation, and excessive extracellular matrix deposition. Although fibroblast activation and proliferation are central drivers of fibrogenesis, the molecular regulators coordinating these processes remain poorly defined. This study investigated fibroblast lineage progression using single-cell RNA-sequencing data from fibroblast-enriched populations in bleomycin-induced mouse models and human IPF samples. In mice, TGF-β signaling was significantly enriched in both activated and proliferative fibroblast subsets. ID3 was identified as a key transcriptional regulator, whose expression closely correlated with augmented TGF-β signaling. Gene regulatory network analysis further suggested that ID3 modulates TGF-β-dependent profibrotic programs. In human IPF, a homologous ID3-high fibroblast population with high proliferative potential was identified, in which ID3 activity was strongly associated with TGF-β signaling. Together, these findings indicate that ID3 promotes fibroblast differentiation and proliferation through the TGF-β signaling pathway, highlighting ID3 as a potential regulator of profibrotic fibroblast progression.
Inhibition of PI3K rebalanced Th1/Th17/Treg and restored macrophage function in imiquimod-induced psoriasis.
Ma D, Zhang X, Mu J … +7 more , Mao K, Chen W, Ran F, Lv R, Ding J, Wang Y, Wen Y
Mol Immunol · 2026 Jun · PMID 42287976 · Publisher ↗
Psoriasis is a chronic immune-mediated skin disease with unmet therapeutic needs. Dysregulated Th1/Th17/Treg cells and M1 macrophage polarization contribute to its pathogenesis, while PI3K/Akt pathway activation is impli...
Psoriasis is a chronic immune-mediated skin disease with unmet therapeutic needs. Dysregulated Th1/Th17/Treg cells and M1 macrophage polarization contribute to its pathogenesis, while PI3K/Akt pathway activation is implicated in psoriatic lesions. This study investigated the therapeutic potential of selective PI3Kδ (CAL-101) and PI3Kγ (AS-605240) inhibitors, alone or combined, using imiquimod-induced psoriatic mice. CAL-101 monotherapy significantly outperformed AS-605240 and combination therapy in mitigating weight loss, splenomegaly, and key histopathological features (hyperkeratosis, acanthosis, inflammatory infiltration). Mechanistically, CAL-101 effectively suppressed PI3K/Akt phosphorylation in skin lesions and restored T-cell homeostasis by rebalancing Th1/Th2/Th17 ratios and enhancing Treg frequency. Conversely, combination therapy paradoxically increased Th17 cells and showed antagonistic effects. Both monotherapies maintained macrophage phagocytic function and suppressed M1 markers (e.g., NOS2, CCL20). While both inhibitors elevated caspase-1, only CAL-101 increased caspase-11; combination therapy uniquely triggered gasdermin D (GSDMD) -mediated pyroptosis. All regimens reversed aberrant MCP-1 upregulation, though CAL-101 was less effective. These findings highlight the superior efficacy of PI3Kδ-specific inhibition over PI3Kγ targeting or dual inhibition in alleviating psoriatic inflammation and immune dysregulation. CAL-101 shows promise as a potential immunomodulatory agent in preclinical models of psoriasis, warranting further investigation into its mechanisms of action.
C1q-targeting bispecific antibodies bypass Fc to trigger complement activation and receptor clustering agonism.
Dijkstra DJ, Blanter MI, van der Meijden E … +5 more , Groenland RJ, Rodriguez C, Bleijlevens B, Beurskens FJ, Trouw LA
Mol Immunol · 2026 Jun · PMID 42285030 · Publisher ↗
Complement-dependent cytotoxicity (CDC) and receptor clustering that triggers outside-in signaling are effector functions employed by various therapeutic antibodies to kill their target cells. However, not all antibodies...
Complement-dependent cytotoxicity (CDC) and receptor clustering that triggers outside-in signaling are effector functions employed by various therapeutic antibodies to kill their target cells. However, not all antibodies, even of the same subclass, efficiently engage these modes of action, because of constraints like antigen density, clustering, and orientation. To overcome these limitations, we developed bispecific antibodies (bsAbs), binding both the classical pathway initiator C1q and cellular targets, aiming to enhance complement activation and enable C1q-driven receptor clustering. Human IgG1 bsAbs were produced, combining four C1q-binding clones with antibodies binding CD20, CD37, HER2, EGFR, GITR and DR5. Antigen binding, complement activation, CDC and receptor clustering were evaluated on various cancer cell lines, including experiments to uncouple Fab-C1q interaction from Fc-C1q interaction. The bsAbs provided more C1q binding and often more complement C3 deposition and CDC than the corresponding monovalent antibody without C1q-binding Fab-arm. Experiments using bsAbs with inactive Fc domain (LALAPG) and bsAb Fab2 fragments indicate that complement activation by these bsAbs do not require the Fc domain. BsAbs with different C1q-targeting Fab-arms all increase C1q binding, but only some enhance complement activation, likely due to the epitope location on C1q. Furthermore, bsAbs strongly induced receptor clustering of GITR and DR5 in presence of C1q, thereby triggering outside-in signaling. We conclude that receptor clustering and complement activation by therapeutic bsAbs through Fab-C1q binding is feasible. The latter can improve complement activation over traditional Fc-mediated activation for mAbs that naturally do not activate complement well.
SLC22A4 as a candidate regulator linking immunity and ferroptosis in septic shock.
Liu L, Yao Y, Ye J … +4 more , Zhuang H, Li Y, Huang Y, Liu C
Mol Immunol · 2026 Jun · PMID 42275906 · Publisher ↗
Septic shock is a life-threatening syndrome characterized by immune dysregulation, oxidative injury, and high mortality. To identify candidate regulators linking immunity and ferroptosis in septic shock, we integrated ex...
Septic shock is a life-threatening syndrome characterized by immune dysregulation, oxidative injury, and high mortality. To identify candidate regulators linking immunity and ferroptosis in septic shock, we integrated expression quantitative trait loci (eQTL)-based Mendelian randomization (MR) with transcriptomic datasets from septic shock patients and controls. Differentially expressed genes overlapping with MR-prioritized genes were further evaluated using 113 machine-learning models, among which the glmBoost plus elastic net model (alpha = 0.9) showed strong discriminatory performance, with area under the curve (AUC) values of 0.999 in GSE26378, 0.980 in GSE26440, and 0.987 in the meta-cohort. The final model retained four risk genes, SERPINB1, DDAH2, SLC22A4, and CEACAM6. Among them, SLC22A4/OCTN1, an ergothioneine transporter, was associated with neutrophil-related immune features and better survival-related outcomes, whereas CEACAM6 showed a distinct pattern associated with immune dysregulation. Protein-ligand docking predicted potential interactions between candidate compounds and selected target proteins. In neutrophil-based validation experiments, SLC22A4 perturbation altered inflammatory cytokine production, STING-associated signaling readouts, and ferroptosis-related markers. Additional transporter-related assays showed that SLC22A4 knockdown reduced intracellular ergothioneine accumulation and that ergothioneine supplementation partially rescued erastin-induced viability loss and lipid ROS accumulation. In a cecal ligation and puncture (CLP) model, D-carnitine hydrochloride, STING-IN-5, and Keap1-Nrf2-IN-9 reshaped inflammatory cytokine responses and were associated with partial attenuation of septic lung injury. These findings suggest that SLC22A4 may represent a candidate regulator connecting immune remodeling with ferroptosis-associated dysfunction in septic shock; however, independent cohort validation, direct in vivo target-engagement studies, and further mechanistic analyses are required before therapeutic translation.
Mycobacterial HBHA drives mitochondrial damage-mediated apoptosis via inhibiting mitophagy in macrophages.
Zhou J, Wu Q, Li W … +5 more , Yang J, Xiao L, Yang Y, Wang N, Feng S
Mol Immunol · 2026 Jun · PMID 42263575 · Publisher ↗
Heparin-binding hemagglutinin adhesin (HBHA), an important adhesion protein located on the surface of Mycobacterium tuberculosis (Mtb), plays a critical role in the pathogen infection process. Macrophages serve as the pr...
Heparin-binding hemagglutinin adhesin (HBHA), an important adhesion protein located on the surface of Mycobacterium tuberculosis (Mtb), plays a critical role in the pathogen infection process. Macrophages serve as the primary effector cells that modulate the host immune response. It has been established that HBHA can regulate macrophage autophagy and apoptosis; however, the precise mechanism underlying HBHA's effect on macrophage apoptosis remains to be fully elucidated. In this study, HBHA was employed to stimulate mouse macrophage RAW 264.7 cells. Subsequently, apoptosis (including DNA fragmentation, the rate of apoptosis, and apoptosis-related proteins), mitochondrial damage (including mitochondrial morphology, membrane potential, and permeability transition), reactive oxygen species (ROS) generation, and mitophagy (including mitochondrial-lysosome formation and mitophagy-related pathway proteins) were systematically evaluated. The ROS scavenger N-acetyl cysteine (NAC) and the mitophagy inducer Carbonylcyanide 3-chlorophenylhydrazone (CCCP) were utilized to investigate the specific mechanism by which HBHA regulates macrophage apoptosis. The results demonstrated that HBHA stimulation significantly promoted apoptosis and ROS production in RAW 264.7 cells, leading to mitochondrial structural damage, decreased membrane potential, and increased permeability. Additionally, HBHA inhibited the formation of mitophagy-lysosome complexes and the activation of mitophagy-related pathways. NAC intervention partially reversed the effects of HBHA on ROS production, mitochondrial dysfunction, and apoptosis in RAW 264.7 cells. However, CCCP intervention effectively suppressed HBHA-induced apoptosis in RAW 264.7 cells by activating mitophagy. HBHA induces mitochondrial damage through the promotion of ROS production and the inhibition of mitophagy, ultimately leading to macrophage apoptosis. Our findings offer a novel perspective on the molecular mechanism by which Mtb evades macrophage immune clearance.
Chitin and its derivative chitosan differently activate porcine innate immune cells.
Guendouz N, Devriendt B
Mol Immunol · 2026 Jun · PMID 42263574 · Publisher ↗
In livestock species such as pigs, antibiotics are frequently used during weaning, a period of increased susceptibility to infections. However, the emergence and spread of antimicrobial resistance necessitate alternative...
In livestock species such as pigs, antibiotics are frequently used during weaning, a period of increased susceptibility to infections. However, the emergence and spread of antimicrobial resistance necessitate alternative strategies to improve animal health. Immune potentiating polysaccharides, including chitin, chitosan, and their derivatives, show promise as functional feed ingredients, yet their direct effects on porcine innate immune cells remain unclear. Here, ex vivo porcine primary neutrophils, monocytes, and monocyte-derived macrophages were used to assess the immunomodulatory properties of structurally distinct chitin-based polymers. In peripheral blood mononuclear cells, neither chitin nor chitosan induced significant secretion of IL-1β, TNF-α, or IL-6, suggesting that only specific subpopulations mediate these effects. Following fractionation, cytokine production was restricted to the CD14⁺ monocyte compartment, where high concentrations of chitosan elicited strong pro-inflammatory responses. To further investigate innate immune programming, trained immunity assays were performed. In monocytes, chitin did not induce training or tolerance, whereas low-molecular-weight, highly deacetylated chitosan promoted a trained phenotype, evidenced by enhanced cytokine production upon lipopolysaccharide restimulation. In contrast, in monocyte-derived macrophages, chitin pretreatment induced a tolerance-like phenotype, characterized by reduced cytokine responses following subsequent stimulation, while chitosan had no significant effect. These findings demonstrate that structural differences in chitin-based polymers determine the magnitude and direction of innate immune responses, supporting their targeted use as functional immunomodulators to enhance health and resilience in livestock.
Combined targeting of mesothelin and tenascin-C enhances CAR-T cell function and tumor microenvironment modulation in ovarian cancer.
Wang X, Zhang D, Wang T … +2 more , Li X, Zhang J
Mol Immunol · 2026 Jun · PMID 42259008 · Publisher ↗
BACKGROUND: The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by dense extracellular matrix deposition and an immunosuppressive tumor microenvironment. Tenascin-C (TNC), an extra...
BACKGROUND: The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by dense extracellular matrix deposition and an immunosuppressive tumor microenvironment. Tenascin-C (TNC), an extracellular matrix protein enriched in ovarian cancer stroma, may provide a stromal cue that restricts T-cell engagement while offering a complementary target to mesothelin (MSLN). This study evaluated whether combined targeting of MSLN and TNC could enhance CAR-T-cell function and remodel the ovarian cancer microenvironment. METHODS: CAR-T cells targeting MSLN and/or TNC were generated using single lentiviral vectors encoding second-generation CAR constructs, including tandem dual-target CARs and MSLN-directed CAR-T cells secreting an anti-TNC single-chain variable fragment with or without a membrane-tethered PD-L1-binding module. CAR expression and function were evaluated across three healthy-donor batches. Target expression on SKOV3 cells and ovarian cancer-associated fibroblasts (CAFs) was validated by flow cytometry and qPCR. Functional studies included NFAT reporter assays, cytokine release, cytotoxicity, immune synapse quantification, adhesion assays, CAF co-culture, and xenograft studies with randomized treatment allocation and blinded tumor measurements. RESULTS: Dual-target TNC+MSLN CAR-T cells demonstrated reproducible CAR expression across donors, enhanced NFAT activation in TNC-rich conditions, increased CD69/CD25 upregulation, and greater IFN-γ, TNF-α, and IL-2 secretion than single-target controls. Compared with MSLN-CAR-T cells, dual-target CAR-T cells showed improved tumor-cell killing, larger and more polarized immune synapses, and stronger tumor-cell adhesion. In CAF co-culture, anti-TNC-secreting CAR-T cells partially reversed suppression, reduced PD-1 and Tim-3 expression, and showed concordant reductions in LAG-3 and TIGIT in exploratory analyses. In vivo, combination stromal targeting delayed tumor growth, increased intratumoral CD4 + and CD8 + infiltration, improved CAR-T persistence, and reduced extracellular matrix deposition and CAF-associated markers. CONCLUSIONS: Combined targeting of MSLN and TNC was associated with improved CAR-T-cell activation and broader microenvironmental remodeling in ovarian cancer models. These data support further evaluation of stromal co-targeting as an adjunct strategy for CAR-T therapy in ovarian cancer, while additional validation of target dependence, safety, and long-term persistence remains necessary.
Restoration of Treg function and polarization of M2 macrophages by tofacitinib to alleviate sarcoidosis through the mediation of the JAK3/STAT5 pathway.
Sheng T, Zhang S, Ma D … +4 more , Jie Y, Wang Y, Ding J, Wen Y
Mol Immunol · 2026 Jun · PMID 42251788 · Publisher ↗
OBJECTIVE: Sarcoidosis is a multisystem granulomatous syndrome with a wide range of clinical features. Tofacitinib, a JAK inhibitor, may become a new treatment for sarcoidosis. The study aimed to elucidate how tofacitini...
OBJECTIVE: Sarcoidosis is a multisystem granulomatous syndrome with a wide range of clinical features. Tofacitinib, a JAK inhibitor, may become a new treatment for sarcoidosis. The study aimed to elucidate how tofacitinib modulates immune responses and reduces granuloma formation in SodA-induced sarcoidosis. METHODS: To evaluate the effects of tofacitinib on granuloma formation, sarcoidosis was induced using SodA peptide, and tofacitinib was administered. The activation of JAK/STAT signaling, pyroptosis, and Th1/Th17/regulatory T cells (Treg) immune profile were detected. Macrophages and Treg were isolated and co-cultured to verify Treg's influence on macrophage polarization. RESULTS: Tofacitinib reduced granulomas in SodA-induced sarcoidosis. It suppressed the activation of JAK3/STAT5 signaling and induced pyroptosis, as evidenced by increased cleaved-Gasdermin D (P = 0.006). Tofacitinib increased the proportions of both M1 and M2-like macrophages, with a predominant shift toward M2-like polarization (P = 0.0014). Notably, tofacitinib restored the ability of Treg cells to induce M2 anti-inflammatory macrophage polarization, leading to reduced IL-1β secretion (P = 0.0183). In addition, tofacitinib reduced the proportions of both Th17 and Treg cells (Th17: P = 0.0022; Treg: P = 0.0021). It did not significantly affect STAT1 or AKT activation. CONCLUSION: Tofacitinib treatment holds potential for mitigating granulomas, likely mediated through the JAK3/STAT5 signaling pathway and the induction of pyroptosis. Furthermore, tofacitinib therapy re-establishes equilibrium within the Th1/Th2/Treg/Th17 immune cell profile, restores the functional capacity of Tregs, and promotes a tendency towards M2 macrophage polarization. These insights contribute to a more comprehensive understanding of the immunomodulatory effects of tofacitinib in the context of sarcoidosis treatment.
Transcription factor STAT1 upregulates IL-36γ to mediate the sensitivity of human nasal epithelial cells to ferroptosis and promote inflammatory progression in chronic rhinosinusitis.
Fan T, Li X
Mol Immunol · 2026 Jun · PMID 42247985 · Publisher ↗
Chronic rhinosinusitis (CRS) is an epidemic disease characterized by persistent inflammation and tissue remodeling of sinus mucosa, and its pathophysiology is still unclear. This study revealed the key role of the signal...
Chronic rhinosinusitis (CRS) is an epidemic disease characterized by persistent inflammation and tissue remodeling of sinus mucosa, and its pathophysiology is still unclear. This study revealed the key role of the signal transducer and activator of transcription 1 (STAT1) /Interleukin-36γ (IL-36γ) signal axis in the pathogenesis of CRS for the first time. In vitro experiments showed that STAT1 overexpression can induce damage to human nasal epithelial cells (HNECs); whereas STAT1 knockdown significantly inhibits Erastin-induced ferroptosis, as evidenced by the restoration of Ferritin Heavy Chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) expression, reduced accumulation of Acyl-CoA Synthetase Long Chain Family Member 4 and Transferrin receptor protein 1 (TFRC) expression, and decreased Malondialdehyde (MDA) content and lipid reactive oxygen species (ROS). The mechanism study showed that STAT1, as a transcription factor, regulated the IL-36γexpression by directly binding to its promoter region, thereby enhancing the sensitivity of HNECs to ferroptosis through the upregulation of IL-36γ. Further experiments found that IL-36γ promoted the release of ferroptosis and inflammatory cytokines, a process potentially involving the p38 MAPK pathway. In the CRS mouse model, the STAT1 inhibitor Fludarabine can effectively alleviate pathological injury, reduce the infiltration of macrophages, CD4 T cells, CD8 T cells, and neutrophils, and mitigate the inflammatory reaction and ferroptosis of the nasal mucosa. This study provides a new perspective for understanding the pathogenesis of CRS, and the discovery of the STAT1/IL-36γ signaling axis also provides a new direction for developing potential therapeutic strategies for CRS.
Myeloid-specific Ythdf2 deletion alleviates acute lung injury by attenuating macrophage inflammation.
Xu J, Meng Q, Ye H … +5 more , Jin C, Yu Y, Chen F, Hu L, Wang J
Mol Immunol · 2026 May · PMID 42217284 · Publisher ↗
Acute lung injury (ALI) is characterized by dysregulated pulmonary inflammation, in which alveolar macrophages (AMs) play a crucial role. The m⁶A reader protein YTHDF2, known to facilitate mRNA degradation, is implicated...
Acute lung injury (ALI) is characterized by dysregulated pulmonary inflammation, in which alveolar macrophages (AMs) play a crucial role. The m⁶A reader protein YTHDF2, known to facilitate mRNA degradation, is implicated in inflammation; however, its specific function in ALI pathogenesis remains unclear. Using myeloid-specific Ythdf2 knockout mice subjected to cecal ligation and puncture (CLP)-induced ALI, we demonstrate that Ythdf2 deficiency significantly attenuates lung injury, as evidenced by reduced histopathological damage, pulmonary edema, and inflammatory cell infiltration, along with lower levels of pro-inflammatory cytokines (IL-6, TNF-α) in both bronchoalveolar lavage fluid and serum. Moreover, Ythdf2 deletion was accompanied by a substantial upregulation of Hmox1 protein expression in both lung tissues and AMs, an observation consistent with the known role of Ythdf2 in pulmonary hypertension. Furthermore, global m⁶A methylation levels and the expression of key methyltransferases (Mettl3, Mettl14) were elevated during ALI, coinciding with increased Ythdf2 expression. This upregulation of m⁶A regulators (YTHDF2, METTL3, METTL14) was also confirmed in pulmonary macrophages from human septic lungs. In conclusion, our findings support the concept that the myeloid-specific deletion of Ythdf2 ameliorates lung injury, an effect closely associated with the upregulation of Hmox1, highlighting Ythdf2 as a potential therapeutic target for ALI.
Butyrate improves dextran sulfate sodium-induced enterotoxicity in broilers.
Bai X, Li R, Quan T … +2 more , Chen Y, Gao T
Mol Immunol · 2026 Jul · PMID 42190407 · Publisher ↗
BACKGROUND: Intestinal inflammation has emerged as a significant global concern in poultry farming, particularly due to its strong association with macrophage imbalance. Research has identified macrophages as critical ta...
BACKGROUND: Intestinal inflammation has emerged as a significant global concern in poultry farming, particularly due to its strong association with macrophage imbalance. Research has identified macrophages as critical target cells for butyrate, which collaboratively maintains intestinal immune homeostasis. This study delves into the regulatory effects of butyrate on macrophages to ameliorate enteritis in broiler chickens. RESULTS: Our findings indicate that broilers treated with dextran sulfate sodium (DSS) exhibit reduced body weight and compromised intestinal mucosal integrity, characterized by increased intestinal permeability, elevated histological scores, diminished goblet cell numbers, reduced secretion of MUC2 protein, and decreased expression of tight junction proteins, alongside heightened oxidative stress and apoptotic responses. Notably, DSS treatment induces the polarization of M0 macrophages towards the pro-inflammatory M1 phenotype, thereby exacerbating intestinal inflammation. Conversely, butyrate supplementation facilitates the polarization of macrophages towards the anti-inflammatory M2 phenotype by inhibiting M1 polarization, thereby mitigating intestinal inflammation and promoting the restoration of the intestinal mucosal barrier. Further in vitro experiments demonstrated that butyrate regulates macrophage polarization through activation of the HDAC3/AMPK/PPARγ/Hippo/GLUT1 signaling pathway, ultimately exerting a beneficial effect. CONCLUSION: Butyrate has been shown to facilitate M2 macrophage polarization by modulating cellular metabolic pathways, thereby ameliorating intestinal inflammation. This study underscores the clinical significance of immunometabolism in intestinal diseases and identifies potential therapeutic targets, serving as a valuable reference for the clinical management of enteritis in broilers.
Role of uridine triggering M2 macrophage polarization to alleviate LPS-induced acute lung injury through the STAT6 signaling pathway.
Wang Y, Guo X, Gao J … +7 more , Wang X, Gao F, He Y, Wang X, Hua Y, Gao Y, Jin F
Mol Immunol · 2026 Jul · PMID 42176493 · Publisher ↗
Acute respiratory distress syndrome (ARDS), the most severe presentation of acute lung injury (ALI), involves diffuse pulmonary inflammation and edema, with hypoxemic respiratory failure as the end result. Given the high...
Acute respiratory distress syndrome (ARDS), the most severe presentation of acute lung injury (ALI), involves diffuse pulmonary inflammation and edema, with hypoxemic respiratory failure as the end result. Given the high mortality and limited therapeutic options, the development of novel interventions is urgently needed. Effective control of excessive pulmonary inflammation and modulation of alveolar macrophage polarization play critical roles in disease progression. In this study, we investigated the therapeutic potential of uridine in alleviating ALI. An in vivo model was established by intratracheal administration of lipopolysaccharide (LPS) in mice, and in vitro experiments were performed using LPS-stimulated MH-S cells. Our results demonstrated that uridine treatment significantly attenuated LPS-induced lung injury, as evidenced by reduced lung index (LI), wet-to-dry weight ratio (W/D), myeloperoxidase (MPO) activity, protein leakage and pro-inflammatory cytokine levels in lung tissues and bronchoalveolar lavage fluid (BALF), along with improved survival in mice. Mechanistically, uridine‑induced M2 polarization of alveolar macrophages was accompanied by STAT6 phosphorylation, suggesting a potential involvement of this pathway. Collectively, these findings suggest that uridine may serve as a promising adjunctive therapeutic agent for ALI, potentially improving disease outcomes through the induction of M2 macrophage polarization.
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