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

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⁺ T lymphocytes. However, p38 MAPK contribution to CD4⁺ T lymphocyte senescence remains less comprehensively characterized and warrants further investigation. This study investigates the contribution of p38 MAPK to senescence in CD4⁺ T lymphocytes, focusing on mitochondrial dysfunction and SASP production to elucidate their pathological potential. Results: Splenic CD4⁺ T lymphocytes isolated from wild-type C57BL/6 mice were subjected to subcytotoxic oxidative stress by H₂O₂ exposure to generate stress-induced premature senescence. H₂O₂-exposed CD4⁺ T lymphocytes exhibited hallmark features of senescence, including increased cell size, reduced cell proliferation, and upregulation of the cell cycle regulators p16^Ink4a and p21^Cip1. Additionally, these cells displayed defective mitophagy, accumulation of dysfunctional mitochondria, and a SASP enriched in Th17-associated cytokines. In senescence-induced CD4⁺ 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⁺ T lymphocytes. These findings ratify the involvement of p38 MAPK as a central regulator of CD4⁺ 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⁺ T lymphocytes and underscores the therapeutic potential of targeting p38 MAPK to mitigate senescence-driven inflammatory diseases.