p38 mitogen-activated protein kinase drives senescence in CD4<sup>+</sup> T lymphocytes and increases their pathological potential

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dc.coverageDOI: 10.1186/s12979-025-00526-8
dc.creatorGonzález-Osuna, Luis
dc.creatorFukada, Sandra Yasuyo
dc.creatorHernández-Cáceres, María Paz
dc.creatorLuz-Crawford, Patricia
dc.creatorCortez, Cristian
dc.creatorRojas, Carolina
dc.creatorCarvajal, Paola
dc.creatorSierra-Cristancho, Alfredo
dc.creatorVernal, Rolando
dc.date2025
dc.date.accessioned2025-11-18T19:55:59Z
dc.date.available2025-11-18T19:55:59Z
dc.description<p>Background: In several diseases, senescent T lymphocytes increase in number and release a senescence-associated secretory phenotype (SASP) with inflammatory and osteoclastogenic potential, favoring inflammation and bone loss. It is well known that the activation of p38 mitogen-activated protein kinase (p38 MAPK) orchestrates senescence in CD8<sup>+</sup> T lymphocytes. However, p38 MAPK contribution to CD4<sup>+</sup> T lymphocyte senescence remains less comprehensively characterized and warrants further investigation. This study investigates the contribution of p38 MAPK to senescence in CD4<sup>+</sup> T lymphocytes, focusing on mitochondrial dysfunction and SASP production to elucidate their pathological potential. Results: Splenic CD4<sup>+</sup> T lymphocytes isolated from wild-type C57BL/6 mice were subjected to subcytotoxic oxidative stress by H<sub>2</sub>O<sub>2</sub> exposure to generate stress-induced premature senescence. H<sub>2</sub>O<sub>2</sub>-exposed CD4<sup>+</sup> T lymphocytes exhibited hallmark features of senescence, including increased cell size, reduced cell proliferation, and upregulation of the cell cycle regulators p16<sup>Ink4a</sup> and p21<sup>Cip1</sup>. Additionally, these cells displayed defective mitophagy, accumulation of dysfunctional mitochondria, and a SASP enriched in Th17-associated cytokines. In senescence-induced CD4<sup>+</sup> T lymphocytes, an increase in the expression of phospho-p38 MAPK was also detected. The senescence changes were reversed when p38 MAPK was blocked using the specific inhibitor BIRB-796. In particular, neutralizing p38 MAPK reduced mitochondrial dysfunction and Th17-type SASP production, demonstrating its critical role in driving these senescent traits in CD4<sup>+</sup> T lymphocytes. These findings ratify the involvement of p38 MAPK as a central regulator of CD4<sup>+</sup> T lymphocyte senescence, particularly concerning the accumulation of dysfunctional mitochondria and pro-inflammatory SASP production. Conclusions: This study provides critical insights into immune aging mechanisms in CD4<sup>+</sup> T lymphocytes and underscores the therapeutic potential of targeting p38 MAPK to mitigate senescence-driven inflammatory diseases.</p>eng
dc.identifierhttps://investigadores.uandes.cl/en/publications/6d334a04-df9c-460d-ab9c-9e779ee7d18b
dc.identifier.urihttps://repositorio.uandes.cl/handle/uandes/59555
dc.languageeng
dc.rightsinfo:eu-repo/semantics/openAccess
dc.sourcevol.22 (2025) nr.1 p.30
dc.subjectCD4-positive T-Lymphocyte
dc.subjectCellular senescence
dc.subjectMitophagy
dc.subjectp38 MAPK
dc.subjectSASP
dc.titlep38 mitogen-activated protein kinase drives senescence in CD4<sup>+</sup> T lymphocytes and increases their pathological potentialeng
dc.typeArticleeng
dc.typeArtículospa
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