MyD88 protein destabilization mitigates NF-κB-dependent protection against macrophage apoptosis

Cell Commun Signal. 2024 Nov 16;22(1):549. doi: 10.1186/s12964-024-01930-1.

Abstract

Various signaling pathways are essential for both the innate immune response and the maintenance of cell homeostasis, requiring coordinated interactions among them. In this study, a mutation in the caspase-1 recognition site within MyD88 abolished inflammasome-dependent negative regulation, causing phenotypic changes in mice with some similarities to human NEMO-deficiencies. The MyD88D162E mutation reduced MyD88 protein levels and colon inflammation in DSS-induced colitis mice but did not affect cytokine expression in bone marrow-derived macrophages (BMDMs). However, compared to MyD88wt counterparts, MyD88D162E BMDMs had increased oxidative stress and dysfunctional mitochondria, along with reduced prosurvival Bcl-xL and BTK expression, rendering cells more prone to apoptosis, exacerbated by ibrutinib treatment. NF-κB activation by lipopolysaccharide mitigated this sensitive phenotype. These findings underscore the importance of MyD88wt signaling for NF-κB activation, protecting against macrophage premature apoptosis at resting state. Targeting MyD88 quantity rather than just its signaling could be a promising strategy for MyD88-driven lymphoma treatment.

Keywords: Apoptosis; Homeostasis; MyD88; NF-κB signaling; Oxidative stress.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / metabolism
  • Colitis / pathology
  • Humans
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL*
  • Myeloid Differentiation Factor 88* / genetics
  • Myeloid Differentiation Factor 88* / metabolism
  • NF-kappa B* / metabolism
  • Protein Stability
  • Signal Transduction

Substances

  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Myd88 protein, mouse