Protein Phosphatase 2A Catalytic Subunit α Plays a MyD88-Dependent, Central Role in the Gene-Specific Regulation of Endotoxin Tolerance

MyD88, the intracellular adaptor of most TLRs, mediates either proinflammatory or immunosuppressive signaling that contributes to chronic inflammation-associated diseases. Although gene-specific chromatin modifications regulate inflammation, the role of MyD88 signaling in establishing such epigenetic landscapes under different inflammatory states remains elusive. Using quantitative proteomics to enumerate the inflammation-phenotypic constituents of the MyD88 interactome, we found that in endotoxin-tolerant macrophages, protein phosphatase 2A catalytic subunit α (PP2Ac) enhances its association with MyD88 and is constitutively activated. Knockdown of PP2Ac prevents suppression of proinflammatory genes and resistance to apoptosis. Through site-specific dephosphorylation, constitutively active PP2Ac disrupts the signal-promoting TLR4-MyD88 complex and broadly suppresses the activities of multiple proinflammatory/proapoptotic pathways as well, shifting proinflammatory MyD88 signaling to a prosurvival mode. Constitutively active PP2Ac translocated with MyD88 into the nuclei of tolerant macrophages establishes the immunosuppressive pattern of chromatin modifications and represses chromatin remodeling to selectively silence proinflammatory genes, coordinating the MyD88-dependent inflammation control at both signaling and epigenetic levels under endotoxin-tolerant conditions. [Display omitted] ► PP2Ac is constitutively activated and targets MyD88 in LPS-tolerized macrophages ► Constitutively active PP2Ac shifts a proinflammatory MyD88 to its prosurvival mode ► Constitutively active PP2Ac reprograms gene-specific chromatin modification landscape ► Constitutively active PP2Ac broadly defines ET at both signaling and epigenetic levels It is unclear exactly how TLR4-induced, gene-specific chromatin modifications that control the inflammation are achieved. Chen and colleagues now reveal that constitutively active PP2Ac in endotoxin-tolerant macrophages acts as a central MyD88-dependent regulator not only to mediate apoptosis resistance but also to “reestablish” the landscape of chromatin modifications and remodeling for gene-specific immunosuppression.