TNFR

TNFR, or tumor necrosis factor receptors, are a group of transmembrane proteins that bind tumor necrosis factor family ligands and initiate signaling pathways that regulate cell survival, apoptosis, and inflammation. They belong to the TNF receptor superfamily, which includes multiple receptors with extracellular cysteine-rich domains.

The two best characterized receptors are TNFR1 (TNFRSF1A, p55) and TNFR2 (TNFRSF1B, p75). TNFR1 is widely expressed throughout many tissues, while TNFR2 expression is more restricted to immune cells and some endothelial and neural tissues. TNFR1 contains a cytoplasmic death domain, whereas TNFR2 lacks a death domain but has motifs for TRAF binding. Both receptors can undergo proteolytic shedding to form soluble TNFRs that can modulate signaling.

Ligands include primarily TNF-α, with lymphotoxin-α (TNF-β) also capable of binding TNFR1 and TNFR2 as a homotrimer; other TNF ligands interact with different members of the same receptor family. Upon ligand binding, TNFR1 typically promotes the assembly of signaling complexes that recruit TRADD, RIPK1, and TRAF2, leading to activation of NF-κB and MAPK pathways, promoting inflammatory gene expression and cell survival. Under certain conditions, death-domain signaling can trigger caspase-8–mediated apoptosis (via Complex II) or, when caspase activity is inhibited, necroptosis. TNFR2 signaling mainly enhances cell survival and proliferation through TRAF2 and cIAPs and can support regulatory T cell function and tissue regeneration.

Physiological and clinical relevance includes regulation of immune responses, hematopoiesis, and tissue homeostasis. Dysregulation is linked to autoimmune and inflammatory diseases and cancer. Therapeutically, blocking TNF signaling with biologics such as etanercept or monoclonal antibodies like infliximab and adalimumab has proven effective in several inflammatory diseases.