International Immunology[JOURNAL]
Sun
200 papers
Increased serum IgG antibody response to Merkel cell polyomavirus oncoproteins in patients with autoimmune rheumatic diseases.
Mazziotta C, Tonnini G, Oimo M … +13 more , Cervellera CF, Badiale G, Touzé A, Assirelli E, Neri S, Ursini F, Rossini M, Adami G, Gatti D, Govoni M, Tognon M, Martini F, Rotondo JC
Int Immunol · 2025 Sep · PMID 40581859 · Publisher ↗
Autoimmune rheumatic diseases (AIRDs) encompass a spectrum of disorders with a partially understood pathogenesis. A role for polyomaviruses in AIRDs occurrence has been reported. However, the involvement of Merkel cell p...
Autoimmune rheumatic diseases (AIRDs) encompass a spectrum of disorders with a partially understood pathogenesis. A role for polyomaviruses in AIRDs occurrence has been reported. However, the involvement of Merkel cell polyomavirus (MCPyV), the main causative factor of Merkel cell carcinoma (MCC), an aggressive skin neoplasm related to immunosuppression, in AIRDs is unknown. The prevalence/serological profiles of immunoglobulin G (IgG) antibodies to MCPyV large and small T (LT/sT) oncoproteins and viral capsid proteins 1 and 2 (VP1/2) were investigated herein in 540 immunosuppressive treatment-naive AIRD patients, encompassing 447 rheumatoid arthritis (RA) and 93 ankylosing spondylitis (AS) patients by seven MCPyV-specific immunoassays. Control sera from 500 healthy subjects (HS) and 128 MCC patients were included. MCPyV DNA and LT/VP1 mRNAs were evaluated in peripheral blood mononuclear cells (PBMCs) from 75 randomly selected AIRD patients. AIRD patients exhibited higher prevalence and levels (optical densities) of serum anti-oncoprotein IgGs (12%-13%, 0.2-0.6) compared to HS (2%-7%, 0.1-0.4), but lower than MCC patients (70%-83%, 0.2-0.7) (P < .05), with the increase being more pronounced in AS (24%-29%, 0.3-0.8) than in RA (9%-11%, 0.2-0.8) (P < .05). Conversely, similar rates and levels of serum anti-capsid proteins IgGs were determined in most cases between study and control groups (60%-73%, 0.1-0.3) (P > .05). Moreover, receiver operating characteristic (ROC) curves indicated that the MCPyV serology can discriminate AIRD patients from HS (P < .0001). A fraction (11%) of AIRD PBMCs tested MCPyV DNA (7.4 ± 2.6 [copy/104 cells]) and mRNA-positive (0.5-0.1 [1/ΔCt]), while matched sera showed high rates and levels of anti-oncoproteins IgGs (38%-75%, 0.2-2). Our study provides the first evidence that AIRD patients are immunologically responsive to MCPyV oncoproteins, with a fraction of these patients presenting an increased presentation of MCPyV LT and sT antigens, possibly due to viral LT/sT oncogene expression in their PBMCs. These data suggest an association between MCPyV infection and AIRDs pathogenesis.
Less severe tumor growth in mice in which mgmt is conditionally deleted using the LysM-Cre system, and the possible impacts of DNA methylation in tumor-associated macrophages.
Phuengmaung P, Saisorn W, Boonmee A … +5 more , Benjaskulluecha S, Amornphimoltham P, Thim-Uam A, Palaga T, Leelahavanichkul A
Int Immunol · 2025 Sep · PMID 40498085 · Publisher ↗
Despite the importance of o6-methylguanine-DNA methyltransferase (MGMT) (a DNA repair enzyme) in cancer cells, the impacts of MGMT in macrophages are still unknown. In mgmt null mice (mgmtflox/flox; LysM-Crecre/-; mgmt d...
Despite the importance of o6-methylguanine-DNA methyltransferase (MGMT) (a DNA repair enzyme) in cancer cells, the impacts of MGMT in macrophages are still unknown. In mgmt null mice (mgmtflox/flox; LysM-Crecre/-; mgmt deletion only in macrophages), subcutaneous administration of MC38 (a murine colon cancer) induced smaller tumors with lower intratumoral CD206-positive cells (mostly M2-like macrophages) than the tumors in littermate controls (mgmt control) (mgmtfl/fl; LysM-Cre-/-), as indicated by immunohistochemistry and flow cytometry. Then, bone marrow-derived macrophages were incubated with lipopolysaccharide (LPS) (M1 polarization), IL-4 (M2 polarization), MC38-conditioned media (tumor-associated macrophages; TAMs), and control media (control). In comparison with control, mgmt was upregulated in all activated cells (M1, M2, and TAMs), with the most prominent in M1. Less prominent M1 pro-inflammation (lower IL-1β and iNOS expression) and M2 polarization (lower Arg-1 expression) in mgmt null macrophages compared with mgmt control were observed. The tumoricidal activity was demonstrated only in M1 (but not M2 and TAMs), and mgmt control M1 was more prominent than mgmt null M1, as evaluated by flow cytometry using flexible 780 viable dye. There was reduced maximal respiration (extracellular flux analysis) with more prominent cell injuries, as indicated by cell-free DNA, oxidative stress (malondialdehyde), and DNA break (phosphohistone H2AX immunohistochemistry), in TAMs from mgmt null when compared with mgmt control. In conclusion, TAM transformation required cell energy and induced DNA injury, which needed the MGMT enzyme for DNA repair. Without MGMT, the abundance of TAMs was too low to promote cancer growth. The use of MGMT inhibitors for cancers is encouraged.
Antigen-presenting cells and lung CD8⁺ resident memory T cells coordinate local immune protection and shape responses to respiratory virus infection.
Kawasaki T, Ikegawa M, Kawai T
Int Immunol · 2025 Nov · PMID 40490946 · Publisher ↗
The respiratory mucosa, encompassing the lungs and nasal tissues, serves as the primary barrier against respiratory viruses. While neutralizing antibodies are effective at preventing viral entry, virus-specific CD8⁺ T ce...
The respiratory mucosa, encompassing the lungs and nasal tissues, serves as the primary barrier against respiratory viruses. While neutralizing antibodies are effective at preventing viral entry, virus-specific CD8⁺ T cells play a vital role in eliminating infected cells and inducing an antiviral state, which curbs disease progression. Among these, CD8⁺ tissue-resident memory T (TRM) cells persist long-term in the lungs, where they serve as first responders and rapidly expand upon secondary respiratory virus infection to provide local protection. The establishment and maintenance of lung CD8⁺ TRM cells require not only local cytokine signals but also antigen presentation. Specific subsets of antigen-presenting cells, such as dendritic cells, alveolar macrophages, monocytes, and endothelial cells also influence the quality and durability of CD8⁺ TRM cell responses. This review summarizes key findings on CD8⁺ T-cell dynamics during respiratory viral infections, with a particular focus on CD8⁺ TRM-cell formation and function. We also highlight the importance of local antigen presentation in driving TRM development and discuss how this knowledge can inform vaccine strategies aimed at eliciting robust, long-lasting mucosal immunity.
Cellular metabolism in Th9, Th17, and Treg cell differentiation.
Kanno T, Nakano K, Endo Y
Int Immunol · 2025 Nov · PMID 40489251 · Full text
CD4+ helper T (Th) cell subsets play an essential role in the regulation of adaptive immunity. Th9, Th17, and regulatory T (Treg) cells require transforming growth factor-beta (TGF-β) for their differentiation; however,...
CD4+ helper T (Th) cell subsets play an essential role in the regulation of adaptive immunity. Th9, Th17, and regulatory T (Treg) cells require transforming growth factor-beta (TGF-β) for their differentiation; however, their respective functions are highly distinct. Recent studies have highlighted the critical role of cellular metabolism in initiating clonal expansion and facilitating the effector differentiation of Th cells. Upon antigen exposure, naïve CD4+ T cells undergo metabolic reprogramming to fulfill their bioenergetic and biosynthetic demands. This process involves a shift from fatty acid oxidation to glycolysis, which ensures a sufficient energy supply for activation and proliferation. Lipid metabolism plays a pivotal role in modulating the differentiation and function of Th17, Treg, and Th9 cells. This review explores the influence of metabolic pathways on key transcription factors, including retinoic-acid-related orphan receptor gamma t (RORγt) and SMADs, and emphasizes their regulatory roles in Th cell differentiation. Furthermore, it discusses emerging therapeutic strategies aimed at targeting cellular metabolism to address autoimmune and inflammatory diseases associated with these T-cell subsets.
Modulating dendritic cell function in allergic asthma with Toxoplasma gondii serine protease inhibitor 1.
Katan Piñeiro J, Soto AS, Farias A … +7 more , Perrone Sibilia M, Sánchez VR, Martin V, Berguer PM, Seigelshifer DJ, Fenoy IM, Goldman A
Int Immunol · 2025 Nov · PMID 40489241 · Publisher ↗
Tolerogenic adjuvants can enhance allergy vaccine efficacy. We previously showed that intranasal administration of recombinant Toxoplasma gondii serine protease inhibitor 1 (rTgPI-1) with ovalbumin alleviates asthma symp...
Tolerogenic adjuvants can enhance allergy vaccine efficacy. We previously showed that intranasal administration of recombinant Toxoplasma gondii serine protease inhibitor 1 (rTgPI-1) with ovalbumin alleviates asthma symptoms in mice. This study investigates the immunomodulatory mechanisms of rTgPI-1, focusing on its effect on dendritic cells (DCs). Bone marrow-derived DCs (BMDCs) were generated in the presence of rTgPI-1 and analyzed for their phenotype. rTgPI-1 exposed BMDCs showed reduced CD80, CD86, and MHCII, increased PDL-1 and CD45Rb, and a higher IL-10/IL-12 ratio. These BMDCs induced fewer CD69⁺CD4⁺ T cells, decreased proliferation and secretion of IL-17 and IL-4, and increased CD4⁺FoxP3⁺ T cells. In vivo, intranasal co-administration of rTgPI-1 with allergen in asthmatic mice reduced CD80high/CD86high DCs, expanded lung CD4⁺FoxP3⁺ regulatory T cells, and decreased the cDC2 subset, correlating with reduced IL-4 levels. Importantly, nafamostat mesylate-a synthetic serine protease inhibitor previously shown to alleviate asthma symptoms-failed to induce FoxP3⁺ T cells both in vitro and in vivo, underscoring the unique tolerogenic activity of rTgPI-1. Finally, stimulation of peripheral blood mononuclear cells from mite-allergic patients with house dust mite extract in the presence of rTgPI-1 led to reduced allergen-specific IL-4 and IL-5 secretion. These findings demonstrate that rTgPI-1 promotes a semimature, tolerogenic DC phenotype, suppresses T cell activation, and fosters regulatory T cell differentiation. Moreover, rTgPI-1 selectively modulates DC subsets in vivo. The observed effects on patient-derived PBMCs support its potential for further preclinical development as an adjuvant for allergen-specific immunotherapy.
The Arf pathway is required for resolving endoplasmic reticulum stress during T-cell activation.
Sumiyoshi M, Kotani Y, Shimokawa C … +8 more , Khueangchiangkhwang S, Maekawa Y, Matsuo Y, Yasukochi Y, Higasa K, Kanaho Y, Watanabe T, Matsuda S
Int Immunol · 2025 Sep · PMID 40405457 · Publisher ↗
Upon antigen recognition, T cells undergo rapid cell proliferation and differentiation, which is accompanied by a drastic change in cellular metabolism. The ADP-ribosylation factor (Arf) pathway contributes to cellular h...
Upon antigen recognition, T cells undergo rapid cell proliferation and differentiation, which is accompanied by a drastic change in cellular metabolism. The ADP-ribosylation factor (Arf) pathway contributes to cellular homeostasis by orchestrating vesicle trafficking, and our previous study using mice lacking both Arf1 and Arf6 (Arf-KO) revealed that Th17-mediated autoimmune diseases were markedly suppressed in Arf-KO mice though the precise mechanism remained elusive. Here, we show that the Arf pathway modulates cellular metabolism in T-cell activation and survival. We found that the lack of Arf1 and Arf6 resulted in hyper-activation of mTOR complex 1 (mTORC1), a master regulator of cellular metabolism, as well as unresolved endoplasmic reticulum (ER) stress, leading to exaggerated apoptosis during T-cell activation. We further demonstrated that treatment with IL-21, a potent inducer of Tfh differentiation, rescued Arf-KO T cells from apoptosis by attenuating ER stress in vitro. Accordingly, antigen-specific antibody production and host defenses against infections such as Leishmania major or Heligmosomoides polygyrus infections were significantly preserved in Arf-KO mice. Taken together, these findings provide mechanistic insights linking the Arf pathway with T-cell homeostasis during activation and identify the Arf pathway as an ideal therapeutic target for autoimmune diseases with a low risk of opportunistic infections.
SLAMF6 regulates basal T cell receptor signaling and influences invariant natural killer T cell lineage diversity.
Endo Y, Hasegawa I, Igi A … +13 more , Onodera A, Mita S, Higashi K, Kurokawa K, Toyoda A, Kiuchi M, Shinzawa M, Wang Y, Koyama-Nasu R, Hirahara K, Motohashi S, Nakayama T, Kimura MY
Int Immunol · 2025 Aug · PMID 40405353 · Full text
Invariant natural killer T (iNKT) cells differentiate into at least three distinct subsets within the thymus, with each subset's frequency varying considerably among mouse strains; however, the molecular mechanisms invol...
Invariant natural killer T (iNKT) cells differentiate into at least three distinct subsets within the thymus, with each subset's frequency varying considerably among mouse strains; however, the molecular mechanisms involved remain unclear. We herein report that iNKT cell lineage diversity results from the significant expansion of iNKT2 cells with limited T cell receptor (TCR) diversity in BALB/c mice and the selection of iNKT1 cells with significantly diverse TCRs in B6 mice. Furthermore, signaling lymphocytic-activation molecule family 6 (SLAMF6) expression on immature thymocytes significantly differs among mouse strains, with the low expression of SLAMF6 on BALB/c immature thymocytes resulting in high "basal TCR signaling" in preselected DP thymocytes, associated with iNKT cell expansion. Our data suggest that the expression level of SLAMF6 on immature thymocytes affects basal TCR signaling in preselected DP thymocytes, which may influence thymocyte development in a T-cell subset.
TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice.
Tanaka R, Murakami Y, Ellis D … +6 more , Seita J, Yinga W, Kakuta S, Kumano K, Fukui R, Miyake K
Int Immunol · 2025 May · PMID 40401698 · Publisher ↗
Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune...
Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune complexes and complement components, significantly contributes to disease morbidity. Although an endosomal single-stranded RNA sensor [Toll-like receptor 7 (TLR7)] is known to drive glomerulonephritis by promoting autoantibody production in B cells, the contribution of macrophage TLR7 responses to glomerulonephritis remains poorly understood. Here, we have examined Tlr7‒/‒ NZBWF1 (New Zealand Black/New Zealand White F1) mice and found that TLR7 deficiency ameliorates lupus nephritis by abolishing autoantibody production against RNA-associated antigens, C3 deposition, and macrophage accumulation in glomeruli. Furthermore, TLR7 signaling increased CD31 expression on glomerular endothelial cells and Ly6Clow macrophages but not on T and B cells, suggesting that CD31 mediates TLR7-dependent migration of monocytes into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single-cell RNA sequencing of glomerular macrophages revealed that TLR7 signaling induced expression of lupus-associated genes, including those encoding Chitinase 3 like 1, ferritin heavy chain 1, IKKε, and complement factor B (CfB). Although serum CfB did not increase in NZBWF1 mice, TLR7-dependent CfB protein expression was detected in glomerular macrophages. In addition, TLR7 signaling promoted C3 cleavage and deposition predominantly on mesangial cells. These findings suggest that TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice.
The impact of Talin2, a signaling protein regulating the focal adhesion complex, on asthma.
Hwang D, An MH, Lee PH … +5 more , Yoon S, Nam Y, Park S, Baek AR, Jang AS
Int Immunol · 2025 Nov · PMID 40401633 · Publisher ↗
Talin protein as a mechanosensitive cytoskeleton protein connects the extracellular matrix to the cytoskeleton by linking to integrins and actin, thereby mediating the conversion of mechanical signals into biochemical si...
Talin protein as a mechanosensitive cytoskeleton protein connects the extracellular matrix to the cytoskeleton by linking to integrins and actin, thereby mediating the conversion of mechanical signals into biochemical signals and influencing disease progression. The biological significance of Talin2 in asthma is not well understood. The aim of this study was to elucidate the role of Talin2 in asthma. Mice sensitized and challenged with ovalbumin (OVA) or saline and MRC-5 cells were used to investigate the role of Talin2 in the pathogenesis of bronchial asthma. In addition, Talin2 levels were measured in the plasma of control subjects and asthmatic patients. The relationships between Talin2 and clinical variables in asthmatic patients were also examined. Plasma Talin2 levels were higher in asthmatic patients than control subjects. In asthmatic patients, Talin2 levels correlated with FEV1 % pred., FVC % pred., and FEV1/FVC, and the blood neutrophils and lymphocyte proportion. The receiver operating characteristic curves for Talin2 levels differed between control subjects and asthmatic patients. Talin2, Kindlin2, Integrin β1 and F-actin levels were significantly increased in MRC-5 cells exposed to Der p 1, but decreased in MRC-5 cells treated with talin2 siRNA. The BALF and serum levels of cytokines (IL-4, IL-5, and TNF-α) were elevated in OVA mice compared to the control mice. Talin2, Kindlin2, Integrin β1, and F-actin protein expression in lung tissue was significantly higher in OVA mice than control mice. These results suggest that Talin2 be involved in the pathogenesis of asthma, and may be a marker for asthma.
Secreted phospholipase A2 regulates intercellular communications by coordinating extracellular phospholipid metabolism.
Murakami M
Int Immunol · 2025 Sep · PMID 40391916 · Full text
Lipids play fundamental roles in life. In essence, "phospholipase A2" (PLA2) indicates a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date,...
Lipids play fundamental roles in life. In essence, "phospholipase A2" (PLA2) indicates a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes that possess PLA2 or related lipid-metabolizing activities have been identified in mammals and are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. Among the PLA2 superfamily, the secreted PLA2 (sPLA2) family contains 11 isoforms in mammals, each of which has unique substrate specificity and tissue/cellular distributions. Recent studies using gene-manipulated (knockout and/or transgenic) mice for a full set of sPLA2s have revealed their diverse roles in immunity, metabolism, and other biological events. Application of mass spectrometric lipidomics to these mice has allowed the identification of target substrates and products of individual sPLA2s in tissue microenvironments. In principle, sPLA2s hydrolyze extracellular phospholipids such as those in extracellular vesicles, microbes, lipoproteins, surfactants, and ingested foods, as well as phospholipids in the plasma membrane of activated or damaged cells, thereby exacerbating or ameliorating various diseases. The actions of sPLA2s are dependent on, or independent of, the generation of free fatty acids, lysophospholipids, or their metabolites (lipid mediators) according to pathophysiological contexts. In this review, I will make an overview of recent understanding of the unexplored immunoregulatory roles of sPLA2s and their underlying lipid pathways, especially focusing on their unique actions on extracellular vesicles, activated/damaged cells, and gut microbiota.
Immunological memory in natural killer cells.
Nabekura T
Int Immunol · 2025 Jul · PMID 40388217 · Publisher ↗
Immune cells are classified into adaptive and innate immune cells. Adaptive immune cells-i.e. T cells and B cells-respond to pathogens in an antigen-specific manner and then provide immunological memory, contributing to...
Immune cells are classified into adaptive and innate immune cells. Adaptive immune cells-i.e. T cells and B cells-respond to pathogens in an antigen-specific manner and then provide immunological memory, contributing to long-term host defense against reinfection. In contrast, innate immune cells promptly respond to pathogens, but they are short-lived and have been thought not to contribute to immunological memory. Natural killer (NK) cells are lymphocytes essential for controlling viral infections and cancer. NK cells-which have traditionally been classified as innate immune cells-have recently been revealed as being capable of differentiating into memory NK cells, thus participating in immunological memory, formerly considered to be restricted to adaptive immune cells. Like memory T and B cells, memory NK cells (i) can be long-lived; (ii) display distinct phenotypes from naïve and activated NK cells; (iii) show augmented cellular functions, as compared with naïve NK cells; (iv) have secondary proliferation capacity; and (v) confer an improved host defense when transferred to naïve recipients. Therefore, at least in a broad sense, they fulfill the definition of immunological memory. In this article, I provide an overview of NK cell memory and recent research trends regarding this phenomenon.
Central compartment of nasal cavity-derived MMP-9 enhances mixed-type 2 inflammation in eosinophilic chronic rhinosinusitis.
Tsuda T, Fujii S, Obata S … +16 more , Takeda K, Hayama M, Maeda Y, Nakatani A, Umeda N, Saito M, Fujii K, Kishikawa T, Tanaka H, Hosokawa K, Sato T, Takenaka Y, Okuzaki D, Nojima S, Ishii M, Inohara H
Int Immunol · 2025 Aug · PMID 40333919 · Publisher ↗
Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper respiratory tract. Although previously classified based on the presence or absence of nasal polyps, it is now commonly classified by endotype. Eosinoph...
Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper respiratory tract. Although previously classified based on the presence or absence of nasal polyps, it is now commonly classified by endotype. Eosinophilic CRS (ECRS) is based on type 2 inflammation and the formation of intractable nasal polyps with eosinophil infiltration. Endoscopic surgery is the preferred treatment modality; however, recurrent cases are common. The central compartment of the nasal cavity has been implicated in these recurrences. Notably, the middle turbinate is considered crucial, but discussions have primarily focused on its anatomical significance. To date, there lacks a biochemical perspective on the role of the middle turbinate in recurrence. In this study, we evaluated the role of the middle turbinate as a source of inflammation in ECRS. Differences in gene expression between ECRS and non-ECRS (NECRS) middle turbinates were evaluated using RNA sequencing. Gene changes induced by MMP-9 stimulation of human nasal epithelial cells were also evaluated by RNA sequencing. Comprehensive analysis showed an enhanced IL-4 signaling pathway in the ECRS middle turbinate. Additionally, gene expression of matrix metalloproteinase-9 (MMP-9) was higher in the middle turbinates of patients with ECRS than in those with NECRS (P = .002). Furthermore, MMP-9 has been found to act on human nasal epithelial cells to enhance pathways such as IL-17, IL-6, and S100 family signaling. MMP-9 in the central compartment of the nasal cavity exacerbates ECRS by induction mixed-type 2 inflammation and airway remodeling.
Differential regulation of type I and II interferon signals by the transcription factor interferon regulatory factor-2 for the generation and function of macrophage populations in the liver.
Yoshizawa K, Yamamoto Y, Takamoto M … +4 more , Tagawa YI, Soejima Y, Sanjo H, Taki S
Int Immunol · 2025 Aug · PMID 40327748 · Publisher ↗
Two major macrophage populations in the steady-state liver, resident Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), contribute crucially to the unique physiological functions of the organ. Much remains to...
Two major macrophage populations in the steady-state liver, resident Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), contribute crucially to the unique physiological functions of the organ. Much remains to be learned, however, about how the differentiation and functions of these cell populations are regulated. We found here that Ly6C-MHCII+ MoMFs were severely reduced in mice lacking interferon (IFN) regulatory factor-2 (IRF-2) (Irf2-/- mice) but restored to the normal frequencies by introducing type I IFN receptor deficiency, indicating that IRF-2 supports MoMF differentiation through attenuating excess type I IFN signals. On the other hand, Irf2-/- KCs developed normally but lacked MHC class II (MHCII) expression. Similar MHCII deficiency in KCs in Il15-/- and Ifng-/- but not Rag1-/- mice pointed to the role for NK cell-derived IFN-γ. Indeed, MHCII expression on resident KCs in Ifng-/- mice was recovered via wild-type NK cells that circulated upon parabiosis as well as by administration of IFN-γ. In contrast, parabiotic restoration of NK cell deficiency in Irf2-/- mice failed to elevate MHCII expression on KCs. Furthermore, Irf2-/- KCs required several times higher amounts of IFN-γ to upregulate MHCII expression than Ifng-/- KCs. Thus, IRF-2 maintains steady-state MHCII expression on KCs by potentiating IFN-γ responses of KCs. Collectively, our current study revealed that IRF-2 plays critical roles in the establishment of the steady state hepatic macrophage system through negative and positive regulation of type I IFN and IFN-γ signaling, respectively.
Zoledronic acid attenuates ischemic brain injury by promoting ETS2 and MSR1 expression.
Otani K, Koyama R, Tsuyama J … +3 more , Sakai S, Hase K, Shichita T
Int Immunol · 2025 Jun · PMID 40305406 · Publisher ↗
Intracerebral inflammation and brain swelling often worsen the functional prognosis of stroke patients. Post-stroke inflammation is resolved by the removal of inflammatogenic damage-associated molecular patterns (DAMPs)...
Intracerebral inflammation and brain swelling often worsen the functional prognosis of stroke patients. Post-stroke inflammation is resolved by the removal of inflammatogenic damage-associated molecular patterns (DAMPs) through macrophage scavenger receptor 1 (MSR1); however, therapeutics promoting MSR1 expression efficiently have not been developed. We identified ETS2 as a transcription factor that promoted MSR1 expression in myeloid cells by epigenetic molecular screening. Increased Ets2 expression in macrophages enhanced MSR1 expression and the internalization of peroxiredoxins (PRXs), pivotal inflammatogenic DAMPs in ischemic stroke. By evaluation of chemicals inducing Ets2 expression, we discovered that zoledronic acid increased Ets2 and Msr1 expression in macrophages. Post-stroke administration of zoledronic acid significantly suppressed cerebral inflammation by increasing MSR1 expression in infiltrating myeloid cells, attenuating ischemic neuronal injury in a myeloid Ets2-dependent manner. Thus, epigenetic molecular screening that enhances MSR1 expression is a useful approach to developing therapeutics that improve functional prognosis after ischemic stroke.
Neuron-microglia interactions modulating neuropathic pain.
Kohno K, Tsuda M
Int Immunol · 2025 Sep · PMID 40251994 · Publisher ↗
Neuropathic pain arises from injury or disease to the sensory nervous system and is characterized by intense pain that is disproportionate to the stimulus. However, effective treatments remain limited, highlighting an ur...
Neuropathic pain arises from injury or disease to the sensory nervous system and is characterized by intense pain that is disproportionate to the stimulus. However, effective treatments remain limited, highlighting an urgent need for novel therapeutic approaches. Over the past two decades, studies have revealed that microglia-resident macrophages in the central nervous system-play an essential role in the development of neuropathic pain. In the dorsal horn of the spinal cord, microglia respond to nerve injury by altering cellular function and interacting with surrounding cells to enhance neuronal excitability that underlies pain hypersensitivity. This review summarizes the microglia-neuron interactions that occur in the spinal dorsal horn after peripheral nerve injury and explores recent findings on the potential of microglia to alleviate neuropathic pain.
Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis.
Shinebaatar E, Morimoto J, Koga R … +5 more , Nguyen TN, Sasaki Y, Yonemura S, Kosako H, Yasutomo K
Int Immunol · 2025 Jul · PMID 40223594 · Full text
Proteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoin...
Proteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and, in certain cases, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse model carrying a mutation in β5i (encoded by Psmb8) along with T-cell-specific β5 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice presented severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice presented impaired proliferative activity with cell cycle arrest in the G0/G1 phase following T cell receptor (TCR) engagement. T cells from KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with the caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without affecting either mitochondrial functions or endoplasmic reticulum (ER) stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only immunodeficiency in PRAAS patients but also T-cell deficiency associated with other disorders.
Immunogenomic precision medicine: a personalized approach based on immunogenomic cancer evolution.
Momoi Y, Kumagai S, Nishikawa H
Int Immunol · 2025 Aug · PMID 40156877 · Publisher ↗
Cancer progression can be understood as a process of diversification and selection (the evolutionary theory of cancer). The immune system also plays a critical role in this process of diversification and selection. The c...
Cancer progression can be understood as a process of diversification and selection (the evolutionary theory of cancer). The immune system also plays a critical role in this process of diversification and selection. The cancer immunoediting hypothesis provides a partial explanation of this evolutionary process; immune-evading cancer clones with genomic and/or epigenomic alterations are selected under the pressure of immune surveillance and immunosuppressive mechanisms are equipped, leading to the development of clinically apparent cancers. Indeed, inflammatory cancers equip immunosuppressive mechanisms in response to the pressure of the immune system. However, recent studies focusing on human cancers have revealed that certain non-inflammatory cancers, which often harbor a single-driver oncogenic mutation, are equipped with immunosuppressive machinery sufficient to evade immune surveillance at the time of malignant transformation. The sequential model of the cancer immunoediting hypothesis is inadequate to explain the development of these non-inflammatory cancers, highlighting the need for a novel concept that can explain their co-evolutionary processes. Moreover, inhibition of oncogenic signaling by specific driver oncogenes has been shown not only to kill cancer cells but also to augment antitumor immunity, suggesting the potential for the advent of molecularly targeted reagents with a variety of immunomodulatory functions from the perspective of personalized therapies. Here, we discuss the processes by which cancer cells and the immune system co-evolve to establish clinically apparent cancers, thereby introducing a new concept of 'immunogenomic cancer evolution', that provides a rationale for the potential of 'immunogenomic cancer precision medicine'.
TAK1 governs monocyte-derived macrophage development in acute sterile peritonitis.
Iwahori K, Maeda K, Sanjo H
Int Immunol · 2025 Jun · PMID 40156848 · Publisher ↗
Monocytes recruited to inflamed tissues differentiate into macrophages, contributing to the resolution of inflammation and tissue repair. However, the mechanisms underlying the development, differentiation, and maturatio...
Monocytes recruited to inflamed tissues differentiate into macrophages, contributing to the resolution of inflammation and tissue repair. However, the mechanisms underlying the development, differentiation, and maturation of these monocyte-derived macrophages (MOMs) remain incompletely understood. Here, we demonstrate that TGFβ-activated kinase 1 (TAK1), a key signaling mediator downstream of various receptors including cytokine receptors and Toll-like receptors, is essential for MOM development. In a zymosan-induced model of acute sterile peritonitis, mice with myeloid-specific deletion of TAK1 exhibited a severe impairment in MOM development within the peritoneal cavity, in contrast to control mice. Blocking death-receptor signaling with neutralizing-antibodies facilitated the recovery of MOM development in these mice, albeit to a limited extent. We identified a transient population of immediate macrophage precursors differentiating from infiltrating monocytes in the peritoneal cavity. Notably, TAK1-deficient macrophage precursors displayed marked susceptibility to cell death, possibly due to a previously unrecognized mechanism distinct from well-characterized cell death pathways. These findings establish TAK1 as a critical regulator of MOM development and uncover a novel survival mechanism in the macrophage precursors during inflammation.
Neural signaling in immunology: the gateway reflex.
Hasebe R, Tanaka H, Yamasaki T … +2 more , Murakami K, Murakami M
Int Immunol · 2025 Jun · PMID 40156845 · Publisher ↗
Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disor...
Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disorders. We here review neural signaling regulating the immune system, with a special focus on the gateway reflex. The gateway reflex is a novel neuro-immune crosstalk mechanism that regulates tissue-specific inflammatory diseases. We have discovered six gateway reflexes so far; all are induced by environmental or artificial stimulations including gravity, electrical stimulation, pain sensation, stress, light, and inflammation in joints. In the presence of increased autoreactive T cells in the blood, such stimulation activates specific neural signaling to release noradrenaline (NA) from the nerve endings at specific blood vessels in the central nervous system. NA activates the interleukin-6 (IL-6) amplifier, which leads to the hyper-activation of nuclear factor-kappa B (NF-κB) in non-immune cells, resulting in the formation of a gateway. This gateway allows autoreactive T cells and other immune cells to accumulate in the target tissue to induce inflammatory diseases. In gateway reflexes induced by stress or remote inflammation, adenosine triphosphate (ATP) secreted from inflammation sites activates specific neural pathways, resulting in organ dysfunction and inflammation in other tissues, suggesting that the gateway reflex regulates tissue-specific inflammatory diseases by bidirectional crosstalk between the neural and immune systems. We also discuss other cases of neural signaling including the inflammatory reflex.
Tertiary lymphoid structures: chronic inflammatory microenvironments in kidney diseases.
Yoshikawa T, Yanagita M
Int Immunol · 2025 Jul · PMID 40127186 · Publisher ↗
Chronic kidney disease is a global health problem with high morbidity and mortality rates. Acute kidney injury substantially increases the risk of chronic kidney disease progression, particularly in the elderly, partly b...
Chronic kidney disease is a global health problem with high morbidity and mortality rates. Acute kidney injury substantially increases the risk of chronic kidney disease progression, particularly in the elderly, partly because of prolonged inflammation that exacerbates kidney fibrosis and dysfunction. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that develop in non-lymphoid organs during chronic inflammation, such as autoimmune diseases, cancers, and age-related inflammation. Age-dependent TLS formation is observed in various organs, such as the kidneys, bladder, lacrimal glands, and liver, potentially contributing to age-related disorders, including chronic kidney disease progression after acute kidney injury. TLSs contain heterogeneous cell populations, such as T cells, B cells, pro-inflammatory fibroblasts, and blood and lymphatic vessels, which orchestrate TLS development and expansion through intensive cell-cell interactions. Pro-inflammatory fibroblasts within TLSs drive TLS formation by producing various chemokines and cytokines that recruit and activate immune cells. Additionally, the CD153-CD30 signaling pathway between senescence-associated T cells and age-associated B cells, both of which increase with age, are essential for renal TLS maturation and expansion, which could be a promising therapeutic target in kidney injury in aged individuals. TLSs also develop in human kidney diseases, such as various glomerulopathies, transplanted kidneys, and renal cell carcinomas, thereby influencing patient outcomes. This review highlights the recent advances in our understanding of the cellular and molecular mechanisms underlying TLS development and pathogenicity, with a focus on age-dependent TLSs in the kidneys. Furthermore, the clinical relevance of TLSs in human kidney diseases is discussed.
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