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Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients. 动物biquity实验表明,局部mmp9 -纤溶酶原轴在犬和患者的炎症性肠病中的重要性。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1093/intimm/dxad006
Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, Yuki Tanaka, Izuru Ohki, Shimpei Kubota, Yuta Shinohara, Yong Bin Teoh, Nozomu Yokoyama, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Takehiko Katsurada, Yoshihiro Matsuno, Shintaro Hojyo, Shigeru Hashimoto, Mitsuyoshi Takiguchi, Masaaki Murakami

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.

利用动物异质性的概念,我们直接将动物表型与人类疾病机制联系起来:基质金属蛋白酶-9 (MMP9)活性引起的局部纤溶酶原水平的降低与狗和炎症性肠病患者肠道炎症的发展有关。我们首先研究了炎症性结肠直肠息肉(ICRPs),这是一种以特发性慢性炎症为特征的犬胃肠道疾病,在微型腊肠(MD)中,通过全外显子组测序发现了31个错义疾病相关的snp。我们在其他10个犬种中对它们进行了测序,发现只有在MD中有5个,分别是PLG、TCOF1、TG、COL9A2和COL4A4。然后我们研究了两个罕见且品种特异性的错义SNP (T/T SNP), PLG: c.477G >T和c.478A>T,发现与没有风险等位基因的icrp相比,具有T/T SNP风险等位基因的icrp在病变中显示出更少的完整的纤溶酶原和纤溶酶活性,但在血清中没有差异。此外,我们发现作为NF-κB靶点的MMP9导致纤溶酶原减少,并且在具有风险等位基因的正常结肠中,表达纤溶酶原分子的肠上皮细胞与表达MMP9的上皮细胞共定位。重要的是,溃疡性结肠炎或克罗恩病患者的MMP9表达也与上皮细胞共定位,表现出NF-κB活化增强和纤溶酶原表达减少。总的来说,我们的动物实验表明,MMP9诱导肠内纤溶酶原减少,促进局部炎症的发展,并表明局部MMP9-纤溶酶原轴是犬和患者的治疗靶点。因此,动物实验可以为生物标志物和治疗靶点提供新的视角。
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引用次数: 1
Correction to: IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway. 修正:IL-17通过PKCβ/Erk1/2/NF-κ b依赖的信号通路参与实验性自身免疫性心肌炎后的心脏纤维化。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1093/intimm/dxac063
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引用次数: 0
Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development. Dupuytren的收缩相关snp增加非免疫细胞(包括成纤维细胞)中SFRP4的表达,从而促进炎症的发展。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1093/intimm/dxad004
Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondo, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei I Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami

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.

Dupuytren's挛缩(DC)是一种以掌腱膜纤维增生性疾病为特征的炎性纤维化,目前尚无有效的治疗方法。尽管一些全基因组关联研究已经确定了与DC相关的风险等位基因,但这些等位基因与发病机制之间的功能联系仍然难以捉摸。我们在此重点研究了与DC相关的两个单核苷酸多态性(snp), rs16879765和rs17171229,在分泌卷曲相关蛋白4 (SFRP4)中。我们研究了SRFP4与IL-6放大器的关联,IL-6放大器放大非免疫细胞中IL-6、生长因子和趋化因子的产生,并通过NF-κB增强加重炎症性疾病。在体外和体内,敲低SFRP4可抑制IL-6放大器的激活,而过表达SFRP4可诱导NF-κ b介导的转录活性的激活。机制上,SFRP4通过直接结合泛素化SFC复合体分子,如IkBα和βTrCP,诱导NF-κB活化,随后IkBα降解。此外,在携带风险等位基因的DC患者的成纤维细胞中,SFRP4的表达显著增加。具有风险等位基因的成纤维细胞一致地增强了IL-6放大器的激活。这些发现表明,IL-6放大器参与了DC的发病机制,特别是在携带SFRP4风险等位基因的患者中。因此,SFRP4是包括DC在内的各种炎症性疾病的潜在治疗靶点。
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引用次数: 1
Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells. 供体B细胞过继移植诱导同种异体移植物耐受:mhc匹配iPS细胞移植的免疫调节策略
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1093/intimm/dxad008
Tomoki Murata, Ryo Otsuka, Airi Sasaki, Tomoki Kamatani, Haruka Wada, Hisashi Yamakawa, Yoshinori Hasegawa, Ken-Ichiro Seino

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.

对于使用诱导多能干细胞(iPSCs)进行细胞或组织移植,从时间和经济成本的角度考虑,正在考虑使用同种异体干细胞。免疫调节是同种异体移植成功的关键问题之一。为了降低排斥反应的风险,已经报道了几种尝试来消除主要组织相容性复合体(MHC)对ipsc衍生移植物的影响。另一方面,我们已经证明,即使MHC的影响减轻了,轻微的抗原诱导的排斥反应也是不可忽视的。在器官移植中,已知供体特异性输血(DST)可以特异性地控制对供体的免疫反应。然而,DST是否能控制ipsc移植的免疫反应尚不清楚。在这项研究中,我们使用小鼠皮肤移植模型,证明在mhc匹配但抗原不匹配的情况下,输注供体脾细胞可以促进同种异体移植物的耐受性。当缩小细胞类型时,我们发现输注分离的脾B细胞足以控制排斥反应。作为一种机制,供体B细胞在受体T细胞中诱导无反应性而非缺失,这表明耐受性是在外周诱导的。供体B细胞输注诱导异基因iPSC移植。这些结果首次表明,使用供体B细胞的DST可能诱导对异体ipsc衍生移植物的耐受性。
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引用次数: 0
Fibronectin on target cells attenuates natural cytotoxicity of NK cells via myeloid immune checkpoint ILT3/LILRB4/gp49B. 靶细胞上的纤维连接蛋白通过骨髓免疫检查点ILT3/LILRB4/gp49B减弱NK细胞的天然细胞毒性。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-07-07 DOI: 10.1093/intimm/dxad012
Fumika Itagaki, Keita Nakatsuka, Haruka Sakai, Shota Endo, Mei-Tzu Su, Toshiyuki Takai

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.

NK细胞通过自然杀伤在先天免疫和抗肿瘤反应中发挥关键作用,其活性受到细胞表面抑制受体的严格调控。免疫球蛋白样转录物3/白细胞免疫球蛋白样受体B4 (ILT3/LILRB4,在小鼠中也称为gp49B)是一种抑制受体,在活化的NK细胞和髓系细胞上表达。人类LILRB4和gp49B的共同生理配体是最近才确定的纤维连接蛋白,特别是n端30kda结构域(FN30)。我们假设LILRB4可以反式结合靶细胞上的纤维连接蛋白,与经典的纤维连接蛋白受体整合素顺式结合,并在NK细胞中传递抑制信号,导致自然杀伤减弱。NK细胞表面gp49B和整合素的流式细胞术和共聚焦显微镜分析表明,这些新型和经典的纤维连接蛋白受体分别与固定在培养板上的纤维连接蛋白共接合。生化分析表明,gp49b缺陷NK细胞与固定纤维连接蛋白结合后,脾脏酪氨酸激酶的酪氨酸磷酸化增强。虽然表面纤维连接蛋白缺乏的YAC-1细胞对gp49b阳性和阴性NK细胞的自然杀伤都很敏感,但在gp49b缺乏的NK细胞中,对富含纤维连接蛋白的Lewis肺癌细胞的杀伤能力增强,而对fn30敲除细胞的杀伤能力则没有增强。这些结果表明,NK细胞的天然细胞毒性通过LILRB4/gp49B感知靶细胞上的纤维连接蛋白而受到负调控,这揭示了LILRB4和纤维连接蛋白在肿瘤微环境中作为NK细胞毒性的潜在衰减剂的意想不到的作用。
{"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}
引用次数: 0
Exploring novel functions of BACH2 in the acquisition of antigen-specific antibodies. 探索BACH2在获得抗原特异性抗体中的新功能。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-05-19 DOI: 10.1093/intimm/dxac065
Kyoko Ochiai, Kazuhiko Igarashi

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.

BACH2 [BTB (broad-complex, tramtrak和bric - brac)和CNC (cap 'n' collar)同源物2]被认为是一种转录抑制因子,在调节免疫细胞分化方面具有广泛的功能。在这里,我们关注BACH2在B细胞中的功能,BACH2首次被证明在免疫系统中发挥重要作用。在B细胞中,BACH2协调基因调控网络,促进抗体的类别转换和亲和成熟,同时抑制浆细胞分化。在这种情况下,BACH2通过调节染色质组织来调节基因表达,并与其他转录因子和染色质调节剂如IRF4(干扰素调节因子4)和PC4(正辅激活因子4)合作。此外,我们最近的观察提出了BACH2具有多种功能的可能性,例如基因激活。由于BACH2的功能障碍导致人类免疫缺陷的发生,揭示BACH2的新功能可能为解决BACH2如何预防这些疾病提供线索。
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引用次数: 2
The role of the microbiota in myelopoiesis during homeostasis and inflammation. 微生物群在平衡和炎症期间骨髓造血过程中的作用。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-05-19 DOI: 10.1093/intimm/dxad002
Yeji Kim, Nobuhiko Kamada

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.

微生物群参与宿主免疫系统的发育和维持。微生物群不仅影响其所在的粘膜组织,还影响远端器官。髓系细胞作为宿主免疫系统的第一反应器,对宿主防御至关重要。它们的生成(称为骨髓造血)受环境信号(包括共生微生物群)的调节。骨髓中的造血干细胞和祖细胞可直接或间接感知微生物群衍生信号,从而在稳态和炎症期间产生髓系细胞。在这篇综述中,我们讨论了共生微生物在骨髓骨髓造血的平衡调节中的作用。我们还概述了炎症和感染期间微生物信号对骨髓造血的影响,尤其关注先天性免疫记忆的发展。研究微生物群与骨髓造血之间的关系将有助于我们了解微生物群如何在局部粘膜之外的系统水平上调节免疫反应。
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引用次数: 0
PCBP1 acts as a regulator of CCL2 expression in macrophages to induce recruitment of monocyte-derived macrophages into the inflamed colon. PCBP1作为巨噬细胞中CCL2表达的调节因子,诱导单核细胞来源的巨噬细胞募集到发炎的结肠。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-05-19 DOI: 10.1093/intimm/dxad003
Xinquan Yang, Toshiki Yabe-Wada, Jia Han, Fumiji Saito, Chie Ogasawara, Sohsuke Yamada, Nobuyuki Onai

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.

具有功能可塑性的肠巨噬细胞通过增加趋化因子和细胞因子在肠道免疫应答中发挥重要作用,从而参与炎症性肠病(IBD)的发病机制。Poly(rC)-binding protein 1 (PCBP1)广泛表达于免疫细胞中,与核酸结合参与mRNA的加工、稳定、翻译和转录。然而,PCBP1对巨噬细胞的影响及其在炎症肠中的具体机制尚不清楚。在这项研究中,巨噬细胞中Pcbp1的条件缺失保护小鼠免受葡聚糖硫酸钠诱导的结肠炎的进展,并导致结肠炎的显著缓解。Pcbp1缺乏显著降低结肠CX3C基序趋化因子受体1+ (CX3CR1+)巨噬细胞的C-C基序趋化因子配体2 (CCL2)的产生,减少炎症结肠中促炎巨噬细胞的积累和促炎细胞因子如IL-6和TNF-α的产生。rna免疫沉淀分析表明PCBP1可能与Ccl2 mRNA相互作用,调控其在巨噬细胞中的表达。炎症肠道中PCBP1的表达也与患者IBD严重程度显著相关,提示PCBP1在肠道炎症中起关键作用。我们预计,我们的研究结果将通过靶向局部微环境中免疫细胞的特定功能,促进IBD新治疗方法的发展,从而有助于减少不良反应。
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引用次数: 0
B cell-intrinsic DNase1L3 is essential for the T cell-independent type II response in mice. B细胞固有的DNase1L3对于小鼠不依赖T细胞的II型应答至关重要。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-05-19 DOI: 10.1093/intimm/dxad001
Kei Kato, Kei Haniuda, Saori Fukao, Daisuke Kitamura

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.

T细胞非依赖性II型(TI-II)抗原,如荚膜多糖,具有多价表位,通过强交联B细胞受体诱导B细胞活化、浆细胞分化和抗体产生。然而,TI-II抗原活化B细胞的机制尚不清楚。在这项研究中,我们证明了DNA内切酶DNase1L3(也称为DNase γ)是TI-II反应所必需的。在免疫TI-II抗原后,dnase1l3缺陷小鼠的抗原特异性抗体的产生严重减少,但免疫T细胞依赖性(TD)抗原时则没有。骨髓嵌合小鼠和B细胞转移实验表明,B细胞内固有的DNase1L3是TI-II应答所必需的。缺乏DNase1L3的B细胞在体内和体外对TI-II的反应中都存在细胞增殖和浆细胞分化的缺陷,而在体外与缺乏DNase1L3的B细胞共培养并不能挽救这种缺陷,这反驳了分泌DNase1L3的参与。TI-II抗原体外刺激可瞬间增加DNase1L3的表达及其在细胞核中的易位。对体内对TI-II抗原有反应的离体B细胞的RNA-seq分析显示,在缺乏dnase1l3的B细胞中,myc靶基因组显著减少。Myc靶基因IRF4的表达在离体dnase1l3缺失的B细胞中减少,在体内,IRF4的强制表达恢复了TI-II反应。这些数据揭示了在TI-II反应中,DNase1L3在B细胞受体信号传导和B细胞激活之间缺失的环节中所起的意想不到的作用,为分子解剖该反应提供了有价值的线索。
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引用次数: 0
Repurposing crizotinib to target RIPK1-dependent cell death. 重新利用克唑替尼靶向ripk1依赖性细胞死亡。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-05-08 DOI: 10.1093/intimm/dxac061
Yajie Yu, Min Li, Shufang Fu, Xiaoyan He, Xinqian Hu, Guofeng Zhu, Jia Wang, Xiaoling You, Yan Mou, Zhi Ye, Jun Wei, Yunhong Zha

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.

受体相互作用蛋白激酶1 (Receptor-interacting protein kinase 1, RIPK1)已成为细胞死亡和炎症的关键调节因子,与许多炎症和退行性疾病的发病机制有关。因此,RIPK1被认为是许多这些疾病的治疗靶点。然而,目前临床上还没有ripk1介导的细胞死亡的药物抑制剂。认识到重新用途的药物具有加速的临床开发管道,在这里,我们对食品和药物管理局(FDA)批准的化合物进行了高通量药物筛选,并确定了克唑替尼作为ripk1依赖性细胞死亡抑制剂的新用途。此外,克唑替尼可挽救TNF-α-诱导的全身炎症反应综合征小鼠的死亡。克里唑替尼直接抑制RIPK1激酶活性。这些发现确定了一种已建立的化合物的新用途,并有望加速ripk1谱系疾病的药物开发。
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International immunology
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