Abstract
Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). In addition, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in upregulation or downregulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.
Highlights
Tumor necrosis factor α (TNFα) is an essential signaling protein in the innate and adaptive immune systems
TNF receptor 2 (TNFR2) knockout led to delayed remyelination and a decreased proliferation and maturation of oligodendrocyte progenitors. These findings provide support for the notion that TNF/TNFR2 serves as principal players in oligodendrocyte regeneration [50]
We considered the TNF receptor 1 (TNFR1) deficiency is consequential to elevated TNFR2 signaling on Tregs, as a result of increased ligand availability as opposed to a loss of stimulatory TNFR1 signaling
Summary
Tumor necrosis factor α (TNFα) is an essential signaling protein in the innate and adaptive immune systems. It plays an important role in tissue degeneration and repair [1]. New evidence suggests that the sTNF-mediated signaling pathway via TNFR1 drives a predominantly pro-inflammatory program whereas mTNF binding to TNFR2 primarily initiates immune modulation and tissue regeneration. These findings suggest that we may selectively target TNFR1 and TNFR2 for therapeutic purposes, providing promise for the context-specific treatment of autoimmune diseases. This review is provided to summarize TNFα and TNFR expression, structure, and signaling pathways, to discuss TNFR1/TNFR2 signaling in autoimmune diseases especially concerning their correlation with Tregs and organ regeneration, as well as to propose treatment strategies aimed at TNFR1/TNFR2 in autoimmune diseases
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