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

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

  • Immun Ageing. 2025 Jul 15;22(1):30. doi: 10.1186/s12979-025-00526-8.
Luis González-Osuna 1,  Sandra Yasuyo Fukada 2,  María Paz Hernández-Cáceres 3 4,  Patricia Luz-Crawford 3,  Cristian Cortez 5 6,  Carolina Rojas 7 8,  Paola Carvajal 9,  Alfredo Sierra-Cristancho 7,  Rolando Vernal 10 11
Affiliations

Affiliations

  • 1 Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. luisgodont@gmail.com.
  • 2 Bone Biology Laboratory, School of Pharmaceutical Sciences, Universidade de São Paulo, Ribeirão Preto, Brazil.
  • 3 Cellular and Molecular Immunology Laboratory, Center for Biomedical Research and Innovation (CiiB), Universidad de Los Andes, Santiago, Chile.
  • 4 Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Santiago, Chile.
  • 5 School of Medical Technology, Faculty of Sciences, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
  • 6 School of Medical Technology, Faculty of Sciences, Universidad de San Sebastián, Santiago, Chile.
  • 7 Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
  • 8 Department of Growth, Development and Public Health, Faculty of Dentistry, Universidad de Los Andes, Santiago, Chile.
  • 9 Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
  • 10 Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. rvernal@uchile.cl.
  • 11 Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago, Chile. rvernal@uchile.cl.
PMID: 40665343 DOI: 10.1186/s12979-025-00526-8
Abstract

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 p16Ink4a and p21Cip1. 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.

Keywords

CD4-positive T-Lymphocyte; Cellular senescence; Mitophagy; SASP; p38 MAPK.

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