International immunology最新文献

{"title":"Neuron-microglia interactions modulating neuropathic pain.","authors":"Keita Kohno, Makoto Tsuda","doi":"10.1093/intimm/dxaf022","DOIUrl":"10.1093/intimm/dxaf022","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"589-598"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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.","authors":"Pornpimol Phuengmaung, Wilasinee Saisorn, Atsadang Boonmee, Salisa Benjaskulluecha, Panomwat Amornphimoltham, Arthid Thim-Uam, Tanapat Palaga, Asada Leelahavanichkul","doi":"10.1093/intimm/dxaf035","DOIUrl":"10.1093/intimm/dxaf035","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"635-654"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Arf pathway is required for resolving endoplasmic reticulum stress during T-cell activation.","authors":"Mami Sumiyoshi, Yui Kotani, Chikako Shimokawa, Sukhonthip Khueangchiangkhwang, Yoichi Maekawa, Yoshiyuki Matsuo, Yoshiki Yasukochi, Koichiro Higasa, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda","doi":"10.1093/intimm/dxaf028","DOIUrl":"10.1093/intimm/dxaf028","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"611-624"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Correlation of interferons and autoimmune aspects in long COVID-19 patients.","authors":"","doi":"10.1093/intimm/dxaf044","DOIUrl":"10.1093/intimm/dxaf044","url":null,"abstract":"","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"655-658"},"PeriodicalIF":3.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secreted phospholipase A2 regulates intercellular communications by coordinating extracellular phospholipid metabolism.","authors":"Makoto Murakami","doi":"10.1093/intimm/dxaf027","DOIUrl":"10.1093/intimm/dxaf027","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"599-610"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased serum IgG antibody response to Merkel cell polyomavirus oncoproteins in patients with autoimmune rheumatic diseases.","authors":"Chiara Mazziotta, Giulia Tonnini, Milena Oimo, Christian Felice Cervellera, Giada Badiale, Antoine Touzé, Elisa Assirelli, Simona Neri, Francesco Ursini, Maurizio Rossini, Giovanni Adami, Davide Gatti, Marcello Govoni, Mauro Tognon, Fernanda Martini, John Charles Rotondo","doi":"10.1093/intimm/dxaf029","DOIUrl":"10.1093/intimm/dxaf029","url":null,"abstract":"<p><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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"625-634"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune responses underpinning acute co-infections with unrelated viruses: timing and location matter.","authors":"Isabelle Jia Hui Foo, Lukasz Kedzierski, Katherine Kedzierska","doi":"10.1093/intimm/dxaf018","DOIUrl":"10.1093/intimm/dxaf018","url":null,"abstract":"<p><p>Immunity to viral infections is generally studied in isolation by measuring immune responses towards a single virus. However, concurrent or sequential viral co-infections can occur in a single host. Viral co-infections can impact anti-viral immunity by altering protective responses and driving immunopathology. Understanding immune mechanisms towards co-infections with unrelated viruses is highly relevant to treatment and prevention. There is, however, a paucity of data on immune responses towards viral co-infections, especially with unrelated viruses. Most commonly studied viral co-infections include chronic viruses, such as hepatitis B, hepatitis C, and human immunodeficiency virus, as well as viruses infecting the same tissues, including respiratory viral co-infections. However, the immunological consequences of co-infections with unrelated acute viruses are less understood, especially for viruses affecting different anatomical sites. As co-infecting viruses can have a more pronounced impact on human health compared to infection with a single virus, understanding immune responses and, especially, the impact of timing, sequence, and location of viral co-infections is of key importance. This review provides an overview of the current knowledge on acute viral co-infections with unrelated viruses, underpinning immune mechanisms, and implications for vaccination regimens.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"507-515"},"PeriodicalIF":3.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central compartment of nasal cavity-derived MMP-9 enhances mixed-type 2 inflammation in eosinophilic chronic rhinosinusitis.","authors":"Takeshi Tsuda, Soichiro Fujii, Sho Obata, Kazuya Takeda, Masaki Hayama, Yohei Maeda, Ayaka Nakatani, Naoki Umeda, Miyu Saito, Kentaro Fujii, Toshihiro Kishikawa, Hidenori Tanaka, Kiyohito Hosokawa, Takashi Sato, Yukinori Takenaka, Daisuke Okuzaki, Satoshi Nojima, Masaru Ishii, Hidenori Inohara","doi":"10.1093/intimm/dxaf025","DOIUrl":"10.1093/intimm/dxaf025","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"551-561"},"PeriodicalIF":3.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunogenomic precision medicine: a personalized approach based on immunogenomic cancer evolution.","authors":"Yusaku Momoi, Shogo Kumagai, Hiroyoshi Nishikawa","doi":"10.1093/intimm/dxaf020","DOIUrl":"10.1093/intimm/dxaf020","url":null,"abstract":"<p><p>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'.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"517-537"},"PeriodicalIF":3.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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.","authors":"Kazuki Yoshizawa, Yuta Yamamoto, Masaya Takamoto, Yoh-Ichi Tagawa, Yuji Soejima, Hideki Sanjo, Shinsuke Taki","doi":"10.1093/intimm/dxaf024","DOIUrl":"10.1093/intimm/dxaf024","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"539-549"},"PeriodicalIF":3.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}