Targeting TNF/TNFR superfamilies in immune-mediated inflammatory diseases

Abstract

Dysregulated signaling from TNF and TNFR proteins is implicated in several immune-mediated inflammatory diseases (IMIDs). This review centers around seven IMIDs (rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, and asthma) with substantial unmet medical needs and sheds light on the signaling mechanisms, disease relevance, and evolving drug development activities for five TNF/TNFR signaling axes that garner substantial drug development interest in these focus conditions. The review also explores the current landscape of therapeutics, emphasizing the limitations of the approved biologics, and the opportunities presented by small-molecule inhibitors and combination antagonists of TNF/TNFR signaling.

Figure 1.

Molecular signaling mechanisms of the focus TNF/TNFR molecules and the anti-inflammatory benefits of their antagonism. TNF: TNF is produced mainly by DAMP/PAMP-activated myeloid cells. Myeloid cells respond to soluble TNF/TNFR1 signaling by recruiting the proinflammatory complex I, orchestrating the release of inflammatory cytokines. Under conditions of loss of cell death checkpoints, TNF/TNFR1 signaling causes the formation of the cytotoxic complex II that precipitates cellular death, fueling chronic inflammation. TNFR2 agonism on Tregs stimulates their proliferation, resulting in immunotolerance via suppression of effector T cells. TL1A: Myeloid activation through inflammatory signals such as TNF induces TL1A expression. This drives T cell effector function, memory cell formation, and IFN production through a Th1/Th17 response. Along with IL-33, TL1A catalyzes the ILC2-mediated Th2 response, and the consequent IL-13 production triggers matrix metalloproteinase production, tissue remodeling, and fibrosis. CD40/CD40L: CD40 signaling results in DC maturation and licensing, causing them to secrete inflammatory cytokines and type I IFN directly and indirectly through CD8⁺ T cell activation and proliferation. CD40 signaling in B cells drives B cell proliferation and differentiation into memory cells and plasma cells that are responsible for autoantibody production. OX40/OX40L: OX40 signaling in T cells drive effector and memory T cell formation and inflammatory cytokine production. In Tregs, OX40 signaling downregulates Foxp3 expression, impairing Treg-mediated effector T cell suppression. BAFF/BAFF-R: Activated myeloid cells produce BAFF that oligomerizes and induces T cell activation and proliferation. BAFF also plays a leading role in costimulating B cells to drive proliferation, differentiation, and autoantibody production. MHC II, major histocompatibility complex II; PAMP, pathogen-associated molecular patterns; TGF-β, transforming growth factor-β.