Statins change the cytokine profile in Trypanosoma cruzi-infected U937 macrophages and murine cardiac tissue through Rho-associated kinases inhibition

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dc.contributor.authorGonzález-Herrera, Fabiola
dc.contributor.authorClayton, Natasha S.
dc.contributor.authorGuzmán-Rivera, Daniela
dc.contributor.authorCarrillo, Ileana
dc.contributor.authorCastillo, Christian
dc.contributor.authorCatalán, Mabel
dc.contributor.authorAnfossi, Renatto
dc.contributor.authorQuintero-Pertuz, Helena
dc.contributor.authorOlea-Azar, Claudio
dc.contributor.authorRivera-Meza, Mario
dc.contributor.authorKemmerling, Ulrike
dc.contributor.authorRidley, Anne J.
dc.contributor.authorVivar, Raúl
dc.contributor.authorMaya, Juan Diego
dc.date.accessioned2023-04-17T18:40:08Z
dc.date.available2023-04-17T18:40:08Z
dc.date.issued2023-01
dc.descriptionIndexación: Scopuses
dc.description.abstractIntroduction: Chronic Chagasic cardiomyopathy (CCC), caused by the protozoan Trypanosoma cruzi, is the most severe manifestation of Chagas disease.CCC is characterized by cardiac inflammation and fibrosis caused by a persistent inflammatory response. Following infection, macrophages secrete inflammatory mediators such as IL-1β, IL-6, and TNF-α to control parasitemia. Although this response contains parasite infection, it causes damage to the heart tissue. Thus, the use of immunomodulators is a rational alternative to CCC. Rho-associated kinase (ROCK) 1 and 2 are RhoA-activated serine/threonine kinases that regulate the actomyosin cytoskeleton. Both ROCKs have been implicated in the polarization of macrophages towards an M1 (pro-inflammatory) phenotype. Statins are FDA-approved lipid-lowering drugs that reduce RhoA signaling by inhibiting geranylgeranyl pyrophosphate (GGPP) synthesis. This work aims to identify the effect of statins on U937 macrophage polarization and cardiac tissue inflammation and its relationship with ROCK activity during T. cruzi infection. Methods: PMA-induced, wild-type, GFP-, CA-ROCK1- and CA-ROCK2-expressing U937 macrophages were incubated with atorvastatin, or the inhibitors Y-27632, JSH-23, TAK-242, or C3 exoenzyme incubated with or without T. cruzi trypomastigotes for 30 min to evaluate the activity of ROCK and the M1 and M2 cytokine expression and secretion profiling. Also, ROCK activity was determined in T. cruzi-infected, BALB/c mice hearts. Results: In this study, we demonstrate for the first time in macrophages that incubation with T. cruzi leads to ROCK activation via the TLR4 pathway, which triggers NF-κB activation. Inhibition of ROCKs by Y-27632 prevents NF-κB activation and the expression and secretion of M1 markers, as does treatment with atorvastatin. Furthermore, we show that the effect of atorvastatin on the NF-kB pathway and cytokine secretion is mediated by ROCK. Finally, statin treatment decreased ROCK activation and expression, and the pro-inflammatory cytokine production, promoting anti-inflammatory cytokine expression in chronic chagasic mice hearts. Conclusion: These results suggest that the statin modulation of the inflammatory response due to ROCK inhibition is a potential pharmacological strategy to prevent cardiac inflammation in CCC. Copyright © 2023 González-Herrera, Clayton, Guzmán-Rivera, Carrillo, Castillo, Catalán, Anfossi, Quintero-Pertuz, Quilaqueo, Olea-Azar, Rivera-Meza, Kemmerling, Ridley, Vivar and Maya.es
dc.description.urihttps://www.frontiersin.org/articles/10.3389/fimmu.2022.1035589/full
dc.identifier.doi10.3389/fimmu.2022.1035589
dc.identifier.issn16643-224
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/48622
dc.language.isoenes
dc.publisherFrontiers Media S.A.es
dc.rights.licenseAtribución 4.0 Internacional (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.subjectChronic chagas cardiomyopathyes
dc.subjectYtokine profilees
dc.subjectMacrophage polarizationes
dc.subjectRho-kinasees
dc.subjectStatinses
dc.subjectTrypanosoma cruzies
dc.titleStatins change the cytokine profile in Trypanosoma cruzi-infected U937 macrophages and murine cardiac tissue through Rho-associated kinases inhibitiones
dc.typeArtículoes
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