p38MAPK guards the integrity of endosomal compartments through regulating necrotic death

Abstract

Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of pathogens, the mechanisms of sensing of pathogen-induced functional perturbations to the host cell remain poorly understood. Here we show that the disruption of endosomal compartments in macrophages by a bacterium or fully synthetic nanoparticles activates stress-response p38MAPK kinase, which triggers execution of cell death of a necrotic type. p38MAPK-mediated necrosis occurs in cells with a compound homozygous deletion of pyroptosis-inducing caspases-1 and -11, apoptotic caspase-8, and necroptosis-inducing receptor-interacting protein kinase-3 (RIPK3), indicating that all of these principal cell death mediators are dispensable for p38MAPK-induced necrosis in response to endosome rupture. p38MAPK-mediated necrosis is suppressed by the receptor-interacting protein kinase 1, RIPK1, and degradation of RIPK1 sensitizes macrophages to necrotic death. Since pathogen-induced cell death of necrotic types is implicated in host defense against infection, our results indicate that functional perturbations in host cells are sensed as a component of the innate immune system.

Single-Cell Epitope-Transcriptomics Reveal Lung Stromal and Immune Cell Response Kinetics to Nanoparticle delivered RIG-I and TLR4 Agonists

“…78,79 NK cells with this transcriptional phenotype ( Pim1, Nfkbia, Gadd45b ) were also reported to be enriched in IL-33 treated mice and were termed “signaling/inflammatory-chemokine-expressing NK cells” in a related scRNA-seq study. 80 Although P38-MAPK signaling is typically associated with cellular proliferation, differentiation, and cell death, 81 it is also involved in NK cell activation, 82 including TLR3-mediated cytokine signaling in response to the PAMP poly(I:C). 83 Given that this change is observed in our data with PAMP treatment via PUUC +/-MPLA, our results further support the concept of Nfkbia, Pim1 , and Gadd45b as markers of a particular form of NK cell activation.…”