FK506 impairs neutrophil migration that results in increased polymicrobial sepsis susceptibility

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dc.contributor.authorBorges, Vanessa de Fátima
dc.contributor.authorGalant, Leticia Selinger
dc.contributor.authorKanashiro, Alexandre
dc.contributor.authorCastanheira, Fernanda Vargas e Silva
dc.contributor.authorMonteiro, Valter Vinícius Silva
dc.contributor.authorDuarte, Diego Ângelo
dc.contributor.authorRodrigues, Filipe Camargo
dc.contributor.authorSilva, Camila Meirelles de Souza
dc.contributor.authorSchneider, Ayda Henriques
dc.contributor.authorCebinelli, Guilherme Cesar Martelossi
dc.contributor.authorde Lima, Mikhael Haruo Fernandes
dc.contributor.authorViola, João Paulo de Biaso
dc.contributor.authorCunha, Thiago Mattar
dc.contributor.authorda Costa Neto, Claudio Miguel
dc.contributor.authorAlves-Filho, José Carlos Farias
dc.contributor.authorPupo, André Sampaio [UNESP]
dc.contributor.authorCunha, Fernando de Queiroz
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionNational Cancer Institute (INCA)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2023-07-29T13:29:25Z
dc.date.available2023-07-29T13:29:25Z
dc.date.issued2023-02-01
dc.description.abstractObjective: This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis. Methods: Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wild-type (WT) mice and mice deficient in the gene Nfat1 (Nfat1−/−) in the C57BL/6 background. Animals were treated with 2.0 mg/kg of FK506, subcutaneously, 1 h before the sepsis model, twice a day (12 h/12 h). The number of bacteria colony forming units (CFU) was manually counted. The number of neutrophils in the lungs was estimated by the myeloperoxidase (MPO) assay. The expression of CXCR2 in neutrophils was determined using flow cytometry analysis. The expression of inflammatory cytokines in macrophage was determined using ELISA. The direct effect of FK506 on CXCR2 internalization was evaluated using HEK-293T cells after CXCL2 stimulation by the BRET method. Results: FK506 treatment potentiated the failure of neutrophil migration into the peritoneal cavity, resulting in bacteremia and an exacerbated systemic inflammatory response, which led to higher organ damage and mortality rates. Failed neutrophil migration was associated with elevated CXCL2 chemokine plasma levels and lower expression of the CXCR2 receptor on circulating neutrophils compared with non-treated CLP-induced septic mice. FK506 did not directly affect CXCL2-induced CXCR2 internalization by transfected HEK-293 cells or mice neutrophils, despite increasing CXCL2 release by LPS-treated macrophages. Finally, the CLP-induced response of Nfat1−/− mice was similar to those observed in the Nfat1+/+ genotype, suggesting that the FK506 effect is not dependent on the NFAT1 pathway. Conclusion: Our data indicate that the increased susceptibility to infection of FK506-treated mice is associated with failed neutrophil migration due to the reduced membrane availability of CXCR2 receptors in response to exacerbated levels of circulating CXCL2.en
dc.description.affiliationDepartment of Pharmacology Ribeirão Preto Medical School University of São Paulo
dc.description.affiliationCenter for Research in Inflammatory Diseases CRID Ribeirão Preto Medical School University of São Paulo
dc.description.affiliationDepartment of Biochemistry and Immunology Ribeirão Preto Medical School University of São Paulo
dc.description.affiliationNational Cancer Institute (INCA)
dc.description.affiliationDepartment of Biophysics and Pharmacology Institute of Biosciences University of São Paulo State (UNESP), Botucatu
dc.description.affiliationUnespDepartment of Biophysics and Pharmacology Institute of Biosciences University of São Paulo State (UNESP), Botucatu
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdFAPESP: 13/08216-2
dc.format.extent203-215
dc.identifierhttp://dx.doi.org/10.1007/s00011-022-01669-w
dc.identifier.citationInflammation Research, v. 72, n. 2, p. 203-215, 2023.
dc.identifier.doi10.1007/s00011-022-01669-w
dc.identifier.issn1420-908X
dc.identifier.issn1023-3830
dc.identifier.scopus2-s2.0-85142232858
dc.identifier.urihttp://hdl.handle.net/11449/247914
dc.language.isoeng
dc.relation.ispartofInflammation Research
dc.sourceScopus
dc.subjectCXCL2
dc.subjectCXCR2
dc.subjectFK506
dc.subjectNeutrophil migration
dc.subjectSepsis
dc.subjectTacrolimus
dc.titleFK506 impairs neutrophil migration that results in increased polymicrobial sepsis susceptibilityen
dc.typeArtigo

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