Emerging functions and therapeutic targets of IL‐38 in central nervous system diseases

Abstract

AbstractInterleukin (IL)‐38 is a newly discovered cytokine of the IL‐1 family, which binds various receptors (i.e., IL‐36R, IL‐1 receptor accessory protein‐like 1, and IL‐1R1) in the central nervous system (CNS). The hallmark physiological function of IL‐38 is competitive binding to IL‐36R, as does the IL‐36R antagonist. Emerging research has shown that IL‐38 is abnormally expressed in the serum and brain tissue of patients with ischemic stroke (IS) and autism spectrum disorder (ASD), suggesting that IL‐38 may play an important role in neurological diseases. Important advances include that IL‐38 alleviates neuromyelitis optica disorder (NMOD) by inhibiting Th17 expression, improves IS by protecting against atherosclerosis via regulating immune cells and inflammation, and reduces IL‐1β and CXCL8 release through inhibiting human microglial activity post‐ASD. In contrast, IL‐38 mRNA is markedly increased and is mainly expressed in phagocytes in spinal cord injury (SCI). IL‐38 ablation attenuated SCI by reducing immune cell infiltration. However, the effect and underlying mechanism of IL‐38 in CNS diseases remain inadequately characterized. In this review, we summarize the biological characteristics, pathophysiological role, and potential mechanisms of IL‐38 in CNS diseases (e.g., NMOD, Alzheimer's disease, ASD, IS, TBI, and SCI), aiming to explore the therapeutic potential of IL‐38 in the prevention and treatment of CNS diseases.