Anti-TNF therapy in the treatment of systemic autoinflammatory diseases: the responses of innate immune cells.

Abstract

Systemic autoinflammatory diseases (SAIDs) are rare conditions resulting from innate immune system dysregulation, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most SAIDs are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor (TNF) is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-TNF therapy is widely used in the clinical management of SAIDs. TNF inhibitors block the interaction of TNF with its two receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). These inhibitors primarily target soluble TNF (sTNF), which mainly binds to TNFR1, exerting anti-inflammatory effects. Interestingly, TNF inhibitors also affect transmembrane TNF (tmTNF), which engages TNFR2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. TNF inhibitors also promote the release of soluble TNFR2 (sTNFR2), which neutralizes circulating TNF. Some agents targeting TNFR2 can even act as agonists, triggering reverse signaling by binding to tmTNF. While effective, prolonged use of TNF inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of TNF receptors. More thoroughly understanding of the mechanisms underlying the action of TNF inhibitors is required to develop more effective and safer treatment for SAIDs. This article reviews current studies on the role of the innate immune system in SAID pathogenesis, the impact of anti-TNF therapy on innate immune cells, and perspectives on developing improved agents targeting TNF or its receptors.