International immunology最新文献

{"title":"Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.","authors":"Takeshi Yamasaki,&nbsp;Noriyuki Nagata,&nbsp;Toru Atsumi,&nbsp;Rie Hasebe,&nbsp;Yuki Tanaka,&nbsp;Izuru Ohki,&nbsp;Shimpei Kubota,&nbsp;Yuta Shinohara,&nbsp;Yong Bin Teoh,&nbsp;Nozomu Yokoyama,&nbsp;Noboru Sasaki,&nbsp;Kensuke Nakamura,&nbsp;Hiroshi Ohta,&nbsp;Takehiko Katsurada,&nbsp;Yoshihiro Matsuno,&nbsp;Shintaro Hojyo,&nbsp;Shigeru Hashimoto,&nbsp;Mitsuyoshi Takiguchi,&nbsp;Masaaki Murakami","doi":"10.1093/intimm/dxad006","DOIUrl":"https://doi.org/10.1093/intimm/dxad006","url":null,"abstract":"<p><p>Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 7","pages":"313-326"},"PeriodicalIF":4.4,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10165198","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: IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway.","authors":"","doi":"10.1093/intimm/dxac063","DOIUrl":"https://doi.org/10.1093/intimm/dxac063","url":null,"abstract":"","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 7","pages":"349-350"},"PeriodicalIF":4.4,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9791807","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":"Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.","authors":"Hiroaki Kida,&nbsp;Jing-Jing Jiang,&nbsp;Yuichiro Matsui,&nbsp;Ikuko Takahashi,&nbsp;Rie Hasebe,&nbsp;Daisuke Kawamura,&nbsp;Takeshi Endo,&nbsp;Hiroki Shibayama,&nbsp;Makoto Kondo,&nbsp;Yasuhiko Nishio,&nbsp;Kinya Nishida,&nbsp;Yoshihiro Matsuno,&nbsp;Tsukasa Oikawa,&nbsp;Shimpei I Kubota,&nbsp;Shintaro Hojyo,&nbsp;Norimasa Iwasaki,&nbsp;Shigeru Hashimoto,&nbsp;Yuki Tanaka,&nbsp;Masaaki Murakami","doi":"10.1093/intimm/dxad004","DOIUrl":"https://doi.org/10.1093/intimm/dxad004","url":null,"abstract":"<p><p>Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 7","pages":"303-312"},"PeriodicalIF":4.4,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10322361","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":"Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells.","authors":"Tomoki Murata,&nbsp;Ryo Otsuka,&nbsp;Airi Sasaki,&nbsp;Tomoki Kamatani,&nbsp;Haruka Wada,&nbsp;Hisashi Yamakawa,&nbsp;Yoshinori Hasegawa,&nbsp;Ken-Ichiro Seino","doi":"10.1093/intimm/dxad008","DOIUrl":"https://doi.org/10.1093/intimm/dxad008","url":null,"abstract":"<p><p>For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 7","pages":"327-338"},"PeriodicalIF":4.4,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149072","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":"Fibronectin on target cells attenuates natural cytotoxicity of NK cells via myeloid immune checkpoint ILT3/LILRB4/gp49B.","authors":"Fumika Itagaki,&nbsp;Keita Nakatsuka,&nbsp;Haruka Sakai,&nbsp;Shota Endo,&nbsp;Mei-Tzu Su,&nbsp;Toshiyuki Takai","doi":"10.1093/intimm/dxad012","DOIUrl":"https://doi.org/10.1093/intimm/dxad012","url":null,"abstract":"<p><p>Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin-like transcript 3/leukocyte immunoglobulin-like receptor B4 (ILT3/LILRB4, also known as gp49B in mice) is an inhibitory receptor expressed on activated NK cells as well as myeloid-lineage cells. The common physiologic ligand of human LILRB4 and gp49B was identified very recently as fibronectin, particularly the N-terminal 30 kDa domain (FN30). We hypothesized that LILRB4 could bind fibronectin on target cells in trans together with integrins, classical fibronectin receptors, in cis and deliver an inhibitory signal in NK cells, leading to attenuated natural killing. Flow cytometric and confocal microscopic analyses of NK cell-surface gp49B and integrins suggested that these novel and classical fibronectin receptors, respectively, co-engage fibronectin immobilized on a culture plate. Biochemical analyses indicated that tyrosine phosphorylation of spleen tyrosine kinase was augmented in gp49B-deficient NK cells upon binding to the immobilized fibronectin. While surface fibronectin-poor YAC-1 cells were evenly sensitive as to natural killing of both gp49B-positive and -negative NK cells, the killing of fibronectin-rich Lewis lung carcinoma cells, but not the FN30-knockout cells, was augmented among gp49B-deficient NK cells. These results suggest that the natural cytotoxicity of NK cells is negatively regulated through LILRB4/gp49B sensing fibronectin on target cells, which sheds light on the unexpected role of LILRB4 and fibronectin as a potential attenuator of NK cell cytotoxicity in the tumor microenvironment.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 7","pages":"339-348"},"PeriodicalIF":4.4,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9782048","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":"Exploring novel functions of BACH2 in the acquisition of antigen-specific antibodies.","authors":"Kyoko Ochiai,&nbsp;Kazuhiko Igarashi","doi":"10.1093/intimm/dxac065","DOIUrl":"https://doi.org/10.1093/intimm/dxac065","url":null,"abstract":"<p><p>BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap 'n' collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class switch and affinity maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively. In addition, our recent observation raises the possibility that BACH2 has diverse functions, such as those in gene activation. Since dysfunction of BACH2 leads to the onset of human immune deficiencies, revealing new functions of BACH2 may give a cue to solve how BACH2 contributes to preventing these diseases.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 6","pages":"257-265"},"PeriodicalIF":4.4,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9535506","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 role of the microbiota in myelopoiesis during homeostasis and inflammation.","authors":"Yeji Kim, Nobuhiko Kamada","doi":"10.1093/intimm/dxad002","DOIUrl":"10.1093/intimm/dxad002","url":null,"abstract":"<p><p>The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation. In this review, we discuss the role of commensal microorganisms in the homeostatic regulation of myelopoiesis in the bone marrow. We also outline the effects of microbial signals on myelopoiesis during inflammation and infection, with a particular focus on the development of innate immune memory. Studying the relationship between the microbiota and myelopoiesis will help us understand how the microbiota regulates immune responses at a systemic level beyond the local mucosa.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 6","pages":"267-274"},"PeriodicalIF":4.4,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9501057","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":"PCBP1 acts as a regulator of CCL2 expression in macrophages to induce recruitment of monocyte-derived macrophages into the inflamed colon.","authors":"Xinquan Yang,&nbsp;Toshiki Yabe-Wada,&nbsp;Jia Han,&nbsp;Fumiji Saito,&nbsp;Chie Ogasawara,&nbsp;Sohsuke Yamada,&nbsp;Nobuyuki Onai","doi":"10.1093/intimm/dxad003","DOIUrl":"https://doi.org/10.1093/intimm/dxad003","url":null,"abstract":"<p><p>Intestinal macrophages with functional plasticity play essential roles in gut immune responses by increasing chemokines and cytokines, thereby contributing to the pathogenesis of inflammatory bowel disease (IBD). Poly(rC)-binding protein 1 (PCBP1), which is widely expressed in immune cells, binds to nucleic acids in mRNA processing, stabilization, translation and transcription. However, little is known about the influence of PCBP1 on macrophages and its specific mechanism in inflamed intestines. In this study, conditional depletion of Pcbp1 in macrophages protected mice from progression of dextran sulfate sodium induced colitis and resulted in significant alleviation of colitis. Pcbp1 deficiency markedly decreased C-C motif chemokine ligand 2 (CCL2) production by colonic CX3C motif chemokine receptor 1+ (CX3CR1+) macrophages and reduced accumulation of pro-inflammatory macrophages and production of pro-inflammatory cytokines, such as IL-6 and TNF-α, in the inflamed colon. RNA-immunoprecipitation analysis indicated that PCBP1 might interact with Ccl2 mRNA and regulate its expression in macrophages. PCBP1 expression in inflamed intestines also correlated significantly with IBD severity in patients, suggesting a critical involvement of PCBP1 in intestinal inflammation. We anticipate that our findings will facilitate the development of novel therapeutic approaches for IBD by targeting the specific function of immune cells in the local microenvironment, thereby helping to reduce adverse effects.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 6","pages":"287-299"},"PeriodicalIF":4.4,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9871101","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":"B cell-intrinsic DNase1L3 is essential for the T cell-independent type II response in mice.","authors":"Kei Kato,&nbsp;Kei Haniuda,&nbsp;Saori Fukao,&nbsp;Daisuke Kitamura","doi":"10.1093/intimm/dxad001","DOIUrl":"https://doi.org/10.1093/intimm/dxad001","url":null,"abstract":"<p><p>T cell independent type II (TI-II) antigens, such as capsular polysaccharides, have multivalent epitopes, which induce B cell activation, plasma cell differentiation and antibody production by strongly cross-linking B cell receptors. However, the mechanism of B cell activation by TI-II antigens remains unclear. In this study, we demonstrate that DNA endonuclease DNase1L3 (also termed DNase γ) is required for the TI-II response. The production of antigen-specific antibodies was severely diminished in DNase1L3-deficient mice upon immunization with TI-II antigens, but not with T cell dependent (TD) antigens. Bone marrow chimeric mice and B cell transfer experiments revealed that B cell-intrinsic DNase1L3 was required for the TI-II response. DNase1L3-deficient B cells were defective in cell proliferation and plasma cell differentiation in the TI-II response in vivo as well as in vitro, which was not rescued by co-culture with DNase1L3-sufficient B cells in vitro, disproving an involvement of a secretory DNase1L3. In vitro stimulation with TI-II antigen transiently increased expression of DNase1L3 and its translocation into the nucleus. RNA-seq analysis of ex vivo B cells that had responded to TI-II antigen in vivo revealed a marked reduction of Myc-target gene sets in DNase1L3-deficient B cells. Expression of IRF4, a gene that Myc targets, was diminished in the ex vivo DNase1L3-deficient B cells, in which forced expression of IRF4 restored the TI-II response in vivo. These data revealed an unexpected role of DNase1L3 in a missing link between B cell receptor signaling and B cell activation in the TI-II response, giving a valuable clue to molecularly dissect this response.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 6","pages":"275-286"},"PeriodicalIF":4.4,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9542886","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":"Repurposing crizotinib to target RIPK1-dependent cell death.","authors":"Yajie Yu,&nbsp;Min Li,&nbsp;Shufang Fu,&nbsp;Xiaoyan He,&nbsp;Xinqian Hu,&nbsp;Guofeng Zhu,&nbsp;Jia Wang,&nbsp;Xiaoling You,&nbsp;Yan Mou,&nbsp;Zhi Ye,&nbsp;Jun Wei,&nbsp;Yunhong Zha","doi":"10.1093/intimm/dxac061","DOIUrl":"https://doi.org/10.1093/intimm/dxac061","url":null,"abstract":"<p><p>Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of Food and Drug Administration (FDA)-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death. Furthermore, crizotinib rescued TNF-α-induced death in mice with systemic inflammatory response syndrome. RIPK1 kinase activity was directly inhibited by crizotinib. These findings identify a new use for an established compound and are expected to accelerate drug development for RIPK1-spectrum disorders.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"35 5","pages":"221-230"},"PeriodicalIF":4.4,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9432476","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}