Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.005
Michael R. Williamson, Benjamin Deneen
Astrocytes respond to all forms of central nervous system maladies. In a recent issue of Nature, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.
{"title":"Astrocytes remember inflammation","authors":"Michael R. Williamson, Benjamin Deneen","doi":"10.1016/j.immuni.2024.04.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.005","url":null,"abstract":"<p>Astrocytes respond to all forms of central nervous system maladies. In a recent issue of <em>Nature</em>, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.011
Lena Hansen, Jenna J. Guthmiller
Humans do not respond equally to vaccination. To investigate why, Mulè et al. developed a multimodal framework and found that high responders after unadjuvanted influenza vaccination exist in a naturally adjuvanted state, mimicking innate immunophenotypes following AS03-adjuvanted vaccination. This highlights biological factors that set apart high-antibody responders and how adjuvants can boost innate immune cues to improve humoral immunity.
{"title":"Immunity by AS03ation: The natural adjuvantage","authors":"Lena Hansen, Jenna J. Guthmiller","doi":"10.1016/j.immuni.2024.04.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.011","url":null,"abstract":"<p>Humans do not respond equally to vaccination. To investigate why, Mulè et al. developed a multimodal framework and found that high responders after unadjuvanted influenza vaccination exist in a naturally adjuvanted state, mimicking innate immunophenotypes following AS03-adjuvanted vaccination. This highlights biological factors that set apart high-antibody responders and how adjuvants can boost innate immune cues to improve humoral immunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.019
Sébastien Trzebanski, Jung-Seok Kim, Niss Larossi, Ayala Raanan, Daliya Kancheva, Jonathan Bastos, Montaser Haddad, Aryeh Solomon, Ehud Sivan, Dan Aizik, Jarmila Sekeresova Kralova, Mor Gross-Vered, Sigalit Boura-Halfon, Tsvee Lapidot, Ronen Alon, Kiavash Movahedi, Steffen Jung
Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.
经典单核细胞(CMs)是在血液中循环的短暂髓系免疫细胞。新的证据表明,CMs 可有不同的本体发生,起源于粒细胞-单核细胞或单核树突状细胞祖细胞(GMPs 或 MDPs)。在此,我们报告了可分离小鼠 GMP 和 MDP 衍生 CMs(即 GMP-Mo 和 MDP-Mo)的表面标记,以及它们的功能特征,包括收养细胞转移后的命运定义。GMP-Mo和MDP-Mo产生的同种异源CM后代(如血液中的非典型单核细胞和肠道巨噬细胞)的增加量相同;但是,这些细胞在硬脑膜和肺等其他选定组织中的播种量不同。具体来说,GMP-Mo 和 MDP-Mo 分化为不同的肺间质巨噬细胞,将 CM 二分法与之前报道的肺巨噬细胞异质性联系起来。总之,我们提供的证据表明,小鼠体内存在两种功能不同的 CM 亚群,它们在体内平衡和受到挑战时对外周组织巨噬细胞群的贡献各不相同。
{"title":"Classical monocyte ontogeny dictates their functions and fates as tissue macrophages","authors":"Sébastien Trzebanski, Jung-Seok Kim, Niss Larossi, Ayala Raanan, Daliya Kancheva, Jonathan Bastos, Montaser Haddad, Aryeh Solomon, Ehud Sivan, Dan Aizik, Jarmila Sekeresova Kralova, Mor Gross-Vered, Sigalit Boura-Halfon, Tsvee Lapidot, Ronen Alon, Kiavash Movahedi, Steffen Jung","doi":"10.1016/j.immuni.2024.04.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.019","url":null,"abstract":"<p>Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.021
Francesco De Sanctis, Silvia Dusi, Simone Caligola, Cristina Anselmi, Varvara Petrova, Barbara Rossi, Gabriele Angelini, Michael Erdeljan, Stefan Wöll, Anna Melissa Schlitter, Thomas Metzler, Katja Steiger, Zea Borok, Peter Bailey, Aline Bauer, Cornelia Halin, Federico Boschi, Rosalba Giugno, Stefania Canè, Rita Lawlor, Vincenzo Bronte
Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.
T淋巴细胞浸润较弱的肿瘤对免疫疗法的反应较差。我们的目标是揭示与恶性肿瘤相关的程序,这些程序调节 T 细胞在肿瘤环境中的进入、停滞和活化。细胞粘附和组织结构程序的差异表达,特别是作为标志性基因的膜四跨蛋白claudin(CLDN)18的存在,将免疫浸润的小鼠胰腺肿瘤与免疫耗竭的小鼠胰腺肿瘤区分开来。在人类胰腺导管腺癌(PDAC)和非小细胞肺癌中,CLDN18的表达与组织学分化程度和良好预后呈正相关。细胞表面的 CLDN18 可促进细胞毒性 T 淋巴细胞(CTL)的增殖,通过肌动蛋白将粘附蛋白 ALCAM 调集到肿瘤细胞膜的脂质筏,从而促进 CTL 与肿瘤细胞的直接接触。这一过程有利于 CTL 与 CLDN18 阳性癌细胞之间形成强大的免疫突触 (IS),从而增加 T 细胞的活化。我们的数据揭示了 CLDN18 在协调 T 细胞浸润和塑造肿瘤免疫环境中的免疫作用。
{"title":"Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer","authors":"Francesco De Sanctis, Silvia Dusi, Simone Caligola, Cristina Anselmi, Varvara Petrova, Barbara Rossi, Gabriele Angelini, Michael Erdeljan, Stefan Wöll, Anna Melissa Schlitter, Thomas Metzler, Katja Steiger, Zea Borok, Peter Bailey, Aline Bauer, Cornelia Halin, Federico Boschi, Rosalba Giugno, Stefania Canè, Rita Lawlor, Vincenzo Bronte","doi":"10.1016/j.immuni.2024.04.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.021","url":null,"abstract":"<p>Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.012
Dominic De Nardo
The ubiquitin-binding endoribonuclease N4BP1 is a critical immunosuppressor, but the mechanism by which it acts to constrain TLR-induced inflammatory cytokine production has remained unclear. In this issue of Immunity, Gitlin et al. find that N4BP1 works in concert with the non-canonical IκB kinase (IKK) to limit activity of the IKK complex.
{"title":"Non-canonical IKKs side with N4BP1 against the family","authors":"Dominic De Nardo","doi":"10.1016/j.immuni.2024.04.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.012","url":null,"abstract":"<p>The ubiquitin-binding endoribonuclease N4BP1 is a critical immunosuppressor, but the mechanism by which it acts to constrain TLR-induced inflammatory cytokine production has remained unclear. In this issue of <em>Immunity</em>, Gitlin et al. find that N4BP1 works in concert with the non-canonical IκB kinase (IKK) to limit activity of the IKK complex.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.03.019
Hannah N. Bell, Brent R. Stockwell, Weiping Zou
Ferroptosis is a type of regulated cell death that drives the pathophysiology of many diseases. Oxidative stress is detectable in many types of regulated cell death, but only ferroptosis involves lipid peroxidation and iron dependency. Ferroptosis originates and propagates from several organelles, including the mitochondria, endoplasmic reticulum, Golgi, and lysosomes. Recent data have revealed that immune cells can both induce and undergo ferroptosis. A mechanistic understanding of how ferroptosis regulates immunity is critical to understanding how ferroptosis controls immune responses and how this is dysregulated in disease. Translationally, more work is needed to produce ferroptosis-modulating immunotherapeutics. This review focuses on the role of ferroptosis in immune-related diseases, including infection, autoimmune diseases, and cancer. We discuss how ferroptosis is regulated in immunity, how this regulation contributes to disease pathogenesis, and how targeting ferroptosis may lead to novel therapies.
{"title":"Ironing out the role of ferroptosis in immunity","authors":"Hannah N. Bell, Brent R. Stockwell, Weiping Zou","doi":"10.1016/j.immuni.2024.03.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.03.019","url":null,"abstract":"<p>Ferroptosis is a type of regulated cell death that drives the pathophysiology of many diseases. Oxidative stress is detectable in many types of regulated cell death, but only ferroptosis involves lipid peroxidation and iron dependency. Ferroptosis originates and propagates from several organelles, including the mitochondria, endoplasmic reticulum, Golgi, and lysosomes. Recent data have revealed that immune cells can both induce and undergo ferroptosis. A mechanistic understanding of how ferroptosis regulates immunity is critical to understanding how ferroptosis controls immune responses and how this is dysregulated in disease. Translationally, more work is needed to produce ferroptosis-modulating immunotherapeutics. This review focuses on the role of ferroptosis in immune-related diseases, including infection, autoimmune diseases, and cancer. We discuss how ferroptosis is regulated in immunity, how this regulation contributes to disease pathogenesis, and how targeting ferroptosis may lead to novel therapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13DOI: 10.1016/j.immuni.2024.04.016
Takashi Imai, Juan Lin, Göksu Gökberk Kaya, Eunjin Ju, Vangelis Kondylis, Konstantinos Kelepouras, Gianmaria Liccardi, Chun Kim, Manolis Pasparakis
RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.
{"title":"The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation","authors":"Takashi Imai, Juan Lin, Göksu Gökberk Kaya, Eunjin Ju, Vangelis Kondylis, Konstantinos Kelepouras, Gianmaria Liccardi, Chun Kim, Manolis Pasparakis","doi":"10.1016/j.immuni.2024.04.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.016","url":null,"abstract":"<p>RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in <em>Ripk1</em><sup>R588E/R588E</sup> cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13DOI: 10.1016/j.immuni.2024.04.018
Marième Ndjim, Imène Gasmi, Fabien Herbert, Charlène Joséphine, Julie Bas, Ali Lamrani, Nathalie Coutry, Sylvain Henry, Valérie S. Zimmermann, Valérie Dardalhon, Marta Campillo Poveda, Evgenia Turtoi, Steeve Thirard, Luc Forichon, Alicia Giordano, Claire Ciancia, Zeinab Homayed, Julie Pannequin, Collette Britton, Eileen Devaney, Philippe Jay
Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.
{"title":"Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity","authors":"Marième Ndjim, Imène Gasmi, Fabien Herbert, Charlène Joséphine, Julie Bas, Ali Lamrani, Nathalie Coutry, Sylvain Henry, Valérie S. Zimmermann, Valérie Dardalhon, Marta Campillo Poveda, Evgenia Turtoi, Steeve Thirard, Luc Forichon, Alicia Giordano, Claire Ciancia, Zeinab Homayed, Julie Pannequin, Collette Britton, Eileen Devaney, Philippe Jay","doi":"10.1016/j.immuni.2024.04.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.018","url":null,"abstract":"<p>Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which <em>lamina propria</em> type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13DOI: 10.1016/j.immuni.2024.03.023
Tyler E. Billipp, Connie Fung, Lily M. Webeck, Derek B. Sargent, Matthew B. Gologorsky, Zuojia Chen, Margaret M. McDaniel, Darshan N. Kasal, John W. McGinty, Kaitlyn A. Barrow, Lucille M. Rich, Alessio Barilli, Mark Sabat, Jason S. Debley, Chuan Wu, Richard Myers, Michael R. Howitt, Jakob von Moltke
Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the “weep” response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.
{"title":"Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance","authors":"Tyler E. Billipp, Connie Fung, Lily M. Webeck, Derek B. Sargent, Matthew B. Gologorsky, Zuojia Chen, Margaret M. McDaniel, Darshan N. Kasal, John W. McGinty, Kaitlyn A. Barrow, Lucille M. Rich, Alessio Barilli, Mark Sabat, Jason S. Debley, Chuan Wu, Richard Myers, Michael R. Howitt, Jakob von Moltke","doi":"10.1016/j.immuni.2024.03.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.03.023","url":null,"abstract":"<p>Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the “weep” response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.1016/j.immuni.2024.04.015
Ying Dong, Jeffrey P. Bonin, Pascal Devant, Zhuoyi Liang, Alexander I.M. Sever, Julian Mintseris, James M. Aramini, Gang Du, Stephen P. Gygi, Jonathan C. Kagan, Lewis E. Kay, Hao Wu
Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.
{"title":"Structural transitions enable interleukin-18 maturation and signaling","authors":"Ying Dong, Jeffrey P. Bonin, Pascal Devant, Zhuoyi Liang, Alexander I.M. Sever, Julian Mintseris, James M. Aramini, Gang Du, Stephen P. Gygi, Jonathan C. Kagan, Lewis E. Kay, Hao Wu","doi":"10.1016/j.immuni.2024.04.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.015","url":null,"abstract":"<p>Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}