{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:23:55Z","timestamp":1776943435913,"version":"3.51.4"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["303044\/2020-9"],"award-info":[{"award-number":["303044\/2020-9"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI116453"],"award-info":[{"award-number":["R01 AI116453"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Programmed cell death (PCD) is an important mechanism of innate immunity against bacterial pathogens. The innate immune PCD pathway involves the molecules caspase-7 and caspase-8, among others. <jats:italic>Brucella abortus<\/jats:italic> is a gram-negative bacterium that causes a zoonotic disease termed brucellosis. The innate immune response against this pathogen involves activation of inflammasome components and induction of pyroptosis. However, no studies so far have revealed the role of caspase-7 or caspase-8 during this bacterial infection. Herein, we demonstrate that caspase-7 is dispensable for caspase-1 processing, IL-1\u03b2 secretion and cell death in macrophages. Additionally, caspase-7 deficient animals control <jats:italic>B. abortus<\/jats:italic> infection as well as the wild type mice. Furthermore, we addressed the role of caspase-8 in inflammasome activation and pyroptosis during this bacterial infection. Macrophages deficient in caspase-8 secreted reduced amounts of IL-1\u03b2 that parallels with diminished caspase-1 activity when compared to wild type cells. Additionally, caspase-8 KO macrophages showed reduced LDH release when compared to wild type, suggesting that caspase-8 may play an important role in pyroptosis in response to <jats:italic>B. abortus<\/jats:italic>. Finally, caspase-8 KO animals were more susceptible to <jats:italic>Brucella<\/jats:italic> infection when compared to wild type mice. Overall, this study contributes to a better understanding of the involvement of caspase-7 and caspase-8 in innate immunity against <jats:italic>B. abortus<\/jats:italic> infection.<\/jats:p>","DOI":"10.3389\/fmicb.2022.1086925","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T05:12:51Z","timestamp":1669871571000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Caspase-8 but not caspase-7 influences inflammasome activation to act in control of Brucella abortus infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Raiany A.","family":"Santos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daiane M.","family":"Cerqueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario S.","family":"Zamboni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio C.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e1000361","DOI":"10.1371\/journal.ppat.1000361","article-title":"Caspase-7 activation by the Nlrc 4\/Ipaf inflammasome restricts legionella pneumophila infection","volume":"5","author":"Akhter","year":"2009","journal-title":"PLoS Pathog."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"20167","DOI":"10.1074\/jbc.M115.652321","article-title":"Caspase-8 as an effector and regulator of NLRP3 Inflammasome signaling","volume":"290","author":"Antonopoulos","year":"2015","journal-title":"J. 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Immunol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2519","DOI":"10.4049\/jimmunol.1400276","article-title":"Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1beta production in response to beta-glucans and the fungal pathogen, Candida albicans","volume":"193","author":"Ganesan","year":"2014","journal-title":"J Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.2353\/ajpath.2010.090503","article-title":"Brucella abortus induces the secretion of proinflammatory mediators from glial cells leading to astrocyte apoptosis","volume":"176","author":"Garcia Samartino","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1189\/jlb.4A0815-346R","article-title":"TLR9 is required for MAPK\/NF-kappa B activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus","volume":"99","author":"Gomes","year":"2016","journal-title":"J. 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Cell Biol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2742","DOI":"10.1182\/blood-2008-09-178038","article-title":"Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival","volume":"113","author":"Lamkanfi","year":"2009","journal-title":"Blood"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"3788","DOI":"10.1038\/s41598-018-21998-3","article-title":"ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.4049\/jimmunol.180.2.1080","article-title":"Central role of MyD88-dependent dendritic cell maturation and proinflammatory cytokine production to control Brucella abortus infection","volume":"180","author":"Macedo","year":"2008","journal-title":"J. Immunol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"5239","DOI":"10.4049\/jimmunol.1301581","article-title":"Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate IL-1beta production","volume":"191","author":"Man","year":"2013","journal-title":"J. Immunol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e1006502","DOI":"10.1371\/journal.ppat.1006502","article-title":"Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip 5\/NLRC4\/ASC inflammasome","volume":"13","author":"Mascarenhas","year":"2017","journal-title":"PLoS Pathog."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1146\/annurev-immunol-042617-053010","article-title":"Apoptosis and clearance of apoptotic cells","volume":"36","author":"Nagata","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.4049\/jimmunol.2200508","article-title":"PANoptosis: a unique innate immune inflammatory cell death modality","volume":"209","author":"Pandian","year":"2022","journal-title":"J. Immunol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1038\/cdd.2013.37","article-title":"AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC","volume":"20","author":"Sagulenko","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"E10888","DOI":"10.1073\/pnas.1809548115","article-title":"Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection","volume":"115","author":"Sarhan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.ceb.2020.02.004","article-title":"New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8","volume":"63","author":"Schwarzer","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.4049\/jimmunol.1302549","article-title":"Cutting edge: endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway","volume":"192","author":"Shenderov","year":"2014","journal-title":"J. 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