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

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