Cell death induced by NLRP3–palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity-tuberculosis comorbidity

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dc.contributor.authorPalma Albornoz, Sandra P
dc.contributor.authorFraga-Silva, Thais FC
dc.contributor.authorde Carvalho, Renan VH
dc.contributor.authorRodrigues, Tamara S
dc.contributor.authorGembre, Ana Flávia
dc.contributor.authorde Oliveira, Rômulo Silva
dc.contributor.authorde Souza, Fernanda Mesquita
dc.contributor.authorCorrêa, Giseli Furlan
dc.contributor.authorRamalho, Leandra NZ
dc.contributor.authorCarlos, Daniela
dc.contributor.authorde Almeida, Danilo C
dc.contributor.authorCâmara, Niels OS
dc.contributor.authorZamboni, Dario S
dc.contributor.authorTakahashi, Viviani Nardini
dc.contributor.authorSorgi, Carlos A
dc.contributor.authorFaccioli, Lucia H
dc.contributor.authorMedeiros, Alexandra I [UNESP]
dc.contributor.authorCosta, Diego Luís
dc.contributor.authorBonato, Vânia LD
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2023-07-29T13:35:10Z
dc.date.available2023-07-29T13:35:10Z
dc.date.issued2023-03-01
dc.description.abstractA low-grade and persistent inflammation, which is the hallmark of obesity, requires the participation of NLRP3 and cell death. During Mycobacterium tuberculosis infection, NLRP3 signaling is important for bacterial killing by macrophages in vitro but was shown to be dispensable for host protection in vivo. We hypothesized that during obesity-tuberculosis (TB) comorbidity, NLRP3 signaling might play a detrimental role by inducing excessive inflammation. We employed a model of high-fat-diet-induced obesity, followed by M. tuberculosis infection in C57BL/6 mice. Obese mice presented increased susceptibility to infection and pulmonary immunopathology compared to lean mice. Using treatment with NLRP3 antagonist and Nlrp3−/− mice, we showed that NLRP3 signaling promoted cell death, with no effect in bacterial loads. The levels of palmitate were higher in the lungs of obese infected mice compared to lean counterparts, and we observed that this lipid increased M. tuberculosis-induced macrophage death in vitro, which was dependent on NLRP3 and caspase-1. At the chronic phase, although lungs of obese Nlrp3−/− mice showed an indication of granuloma formation compared to obese wild-type mice, there was no difference in the bacterial load. Our findings indicate that NLRP3 may be a potential target for host-directed therapy to reduce initial and severe inflammation-mediated disease and to treat comorbidity-associated TB. © 2022 The Pathological Society of Great Britain and Ireland.en
dc.description.affiliationBasic and Applied Immunology Program Ribeirao Preto Medical School University of Sao Paulo
dc.description.affiliationDepartment of Biochemistry and Immunology Ribeirao Preto Medical School University of Sao Paulo
dc.description.affiliationDepartment of Pathology and Legal Medicine Ribeirao Preto Medical School University of Sao Paulo
dc.description.affiliationDepartment of Immunology Institute of Biomedical Sciences IV University of Sao Paulo
dc.description.affiliationDepartment of Cell Biology Ribeirao Preto Medical School University of Sao Paulo
dc.description.affiliationDepartment of Clinical Analysis Toxicology and Bromatology School of Pharmaceutical Sciences of Ribeirão Preto University of Sao Paulo
dc.description.affiliationDepartment of Biological Sciences School of Pharmaceutical Sciences São Paulo State University
dc.description.affiliationUnespDepartment of Biological Sciences School of Pharmaceutical Sciences São Paulo State University
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdFAPESP: 2015/00658-1
dc.description.sponsorshipIdFAPESP: 2015/00774-1
dc.description.sponsorshipIdFAPESP: 2017/21629-5
dc.format.extent291-303
dc.identifierhttp://dx.doi.org/10.1002/path.6041
dc.identifier.citationJournal of Pathology, v. 259, n. 3, p. 291-303, 2023.
dc.identifier.doi10.1002/path.6041
dc.identifier.issn1096-9896
dc.identifier.issn0022-3417
dc.identifier.scopus2-s2.0-85145414402
dc.identifier.urihttp://hdl.handle.net/11449/248126
dc.language.isoeng
dc.relation.ispartofJournal of Pathology
dc.sourceScopus
dc.subjectcell death
dc.subjecthost-directed therapy
dc.subjectimmunopathology
dc.subjectMycobacterium tuberculosis
dc.subjectNLRP3
dc.subjectobesity
dc.titleCell death induced by NLRP3–palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity-tuberculosis comorbidityen
dc.typeArtigo
unesp.author.orcid0000-0001-9638-8529[1]
unesp.author.orcid0000-0002-2053-8938[2]
unesp.author.orcid0000-0001-5740-0652[3]
unesp.author.orcid0000-0002-4968-5384[4]
unesp.author.orcid0000-0002-6329-0506[8]
unesp.author.orcid0000-0002-3486-5294[9]
unesp.author.orcid0000-0001-8144-2238[10]
unesp.author.orcid0000-0003-3661-2124[11]
unesp.author.orcid0000-0001-5436-1248[12]
unesp.author.orcid0000-0002-7856-7512[13]
unesp.author.orcid0000-0002-5092-3423[14]
unesp.author.orcid0000-0001-7528-9935[15]
unesp.author.orcid0000-0002-4999-8305[16]
unesp.author.orcid0000-0001-6048-3647[17]
unesp.author.orcid0000-0002-9440-2814[18]
unesp.author.orcid0000-0003-4189-2685[19]

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