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p38γ and p38δ modulate innate immune response by regulating MEF2D activation

Alejandra Escós1, Ester Diaz-Mora1, Michael Pattison2

  • 1Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC (CNB-CSIC), Campus-UAM, Madrid, Spain.

Elife
|July 17, 2023
PubMed

Insights

p38γ/p38δ kinases regulate innate immunity. New kinase-inactive p38γ/p38δ mice reveal their role in inflammatory responses and MEF2D phosphorylation, crucial for immune gene expression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • p38γ and p38δ (p38γ/p38δ) kinase roles in inflammation are unclear due to TPL2 level alterations in deficient mice.
  • TPL2 is critical for myeloid cell inflammation regulation.

Purpose of the Study:

  • To elucidate specific p38γ/p38δ functions in innate immunity.
  • To investigate the role of p38γ/p38δ in regulating inflammatory responses and gene expression.

Main Methods:

  • Generation of kinase-inactive p38γ/p38δ (p38γ/δKIKO) mice with normal TPL2 levels.
  • Assessment of inflammatory responses to lipopolysaccharide (LPS) and *Candida albicans* infection.
  • Gene expression, phospho-proteomic, and in vitro kinase assays.

Main Results:

  • p38γ/δKIKO mice exhibited reduced inflammatory responses and septic shock susceptibility.
  • p38γ/p38δ kinases regulate numerous innate immune response genes.
  • p38γ/p38δ phosphorylate MEF2D at Ser444, impacting its transcriptional activity and downstream gene expression (Nos2, Il1b).

Conclusions:

  • p38γ/p38δ kinases are key regulators of innate immune responses.
  • MEF2D phosphorylation by p38γ/p38δ is a critical mechanism controlling immune gene expression.
Keywords:
MAPKMEF2Dbiochemistrychemical biologyimmunologyinflammationmousep38γp38δphosphorylation

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