p38γ and p38δ modulate innate immune response by regulating MEF2D activation

  1. Alejandra Escós
  2. Ester Diaz-Mora
  3. Michael Pattison
  4. Pilar Fajardo
  5. Diego González-Romero
  6. Ana Risco
  7. José Martín-Gómez
  8. Éric Bonneil
  9. Nahum Sonenberg
  10. Seyed Mehdi Jafarnejad
  11. Juan José Sanz-Ezquerro
  12. Steven C Ley
  13. Ana Cuenda  Is a corresponding author
  1. Centro Nacional de Biotecnología/CSIC, Spain
  2. The Francis Crick Institute, United Kingdom
  3. Université de Montréal, Canada
  4. McGill University, Canada
  5. Queen's University Belfast, United Kingdom
  6. University College London, United Kingdom

Abstract

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using Mapk12/Mapk13 deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a Mapk12D171A/D171A/Mapk13-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and Candida albicans infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of Nos2 and Il1b mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Alejandra Escós

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
  2. Ester Diaz-Mora

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
  3. Michael Pattison

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Pilar Fajardo

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
  5. Diego González-Romero

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0564-3326
  6. Ana Risco

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
  7. José Martín-Gómez

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
  8. Éric Bonneil

    Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.
  9. Nahum Sonenberg

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    Nahum Sonenberg, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4707-8759
  10. Seyed Mehdi Jafarnejad

    Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5129-7081
  11. Juan José Sanz-Ezquerro

    Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9084-6354
  12. Steven C Ley

    Institute of Immunity and Transplantation, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5911-9223
  13. Ana Cuenda

    Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    For correspondence
    acuenda@cnb.csic.es
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9013-5077

Funding

Ministerio de Ciencia e Innovación (PID2019-108349RB-100)

  • Juan José Sanz-Ezquerro
  • Ana Cuenda

Ministerio de Ciencia e Innovación (SAF2016-79792R)

  • Juan José Sanz-Ezquerro
  • Ana Cuenda

Wellcome Trust (FC001103)

  • Steven C Ley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were housed in specific pathogen‐free conditions in the CNB‐CSIC animal house. Animal procedures were performed in accordance with national and EU guidelines, with the approval of the Centro Nacional de Biotecnología Animal Ethics Committee, CSIC and Comunidad de Madrid (Reference: PROEX 316/15 and PROEX 071/19).

Copyright

© 2023, Escós et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alejandra Escós
  2. Ester Diaz-Mora
  3. Michael Pattison
  4. Pilar Fajardo
  5. Diego González-Romero
  6. Ana Risco
  7. José Martín-Gómez
  8. Éric Bonneil
  9. Nahum Sonenberg
  10. Seyed Mehdi Jafarnejad
  11. Juan José Sanz-Ezquerro
  12. Steven C Ley
  13. Ana Cuenda
(2023)
p38γ and p38δ modulate innate immune response by regulating MEF2D activation
eLife 12:e86200.
https://doi.org/10.7554/eLife.86200

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https://doi.org/10.7554/eLife.86200