TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity

Abstract

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an anti-inflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical co-purification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloidspecific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously-unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε anti-inflammatory pathway.

Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF

“…Therefore, a pathway common to the IL1R and TNF receptors is activated to block M2 gene expression downstream of STAT6. Recent results showed the type 2 TNF receptor is involved in the control of M2 gene expression and indeed, loss of TNFR2 caused altered Arg1 and Mgl2 expression in M2 polarization conditions ( Fu et al, 2021 ). However, when we used BMDMs lacking the TNFR1, TNF-mediated suppression of Retnla was completely lost ( Fig 5D ).…”

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

“…In addition to microglia, astrocytes are the largest and most abundant glial cells in the CNS, contributing to the maintenance of its health and function, which have also been implicated in the onset and progression of several neurodegenerative diseases [ 55 , 56 ]. Recently, we reported that PGRN mediated the macrophage polarization and switch [ 57 ], suggesting the critical role of PGRN in macrophage-mediated inflammation. In this study, we revealed that the brains of PGRN-deficient mice displayed enhanced activation of microglia and astrocytes compared with age-matched WT mice, further indicating the critical role of PGRN in regulating systematic inflammation in CNS.…”

Targeting TNFR2 in Cancer: All Roads Lead to Rome

“…tmTNFα+ M2 macrophages were more potent in inducing Treg differentiation and proliferation ( 48 ). 14-3-3ϵ was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch ( 76 ).…”