Innate lymphoid cells in inflammatory arthritis

Abstract

Aberrant activation and dysregulation of immune system is a common feature of many forms of inflammatory arthritis. Since their identification as a distinctive population of leukocytes, innate lymphoid cells (ILCs) have been considered crucial in maintaining tissue homeostasis and bridges between innate and adaptive immune system. Altered ILCs' subset distribution and function have been observed in a variety of autoimmune and chronic inflammatory diseases and suggest a subset-specific role of ILCs in the pathogenesis of immune-mediated inflammation. In this review, we focus on the current knowledge of ILC subset and their role in inflammatory arthritis, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), enteropathic arthritis, and other seronegative spondyloarthritis. By better understanding the biology and function of ILC subset in different disease settings, new therapeutic interventions can be anticipated by modulating dysregulated ILC responses toward promoting resolution of inflammation.

Keywords: Innate lymphoid cells; Rheumatoid arthritis; Spondyloarthritis.

Fig. 1

The role of different ILC subsets in RA. Damage in the epithelium cells leads to the release of alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which strongly induces ILC2 differentiation and subsequent Th2 activation by producing IL-4, IL-5, and IL-13. ILC2s proliferate under IL-9 stimulation and activate regulatory T cells (Treg) via binding of glucocorticoid-induced TNFR-related protein (GITR) ligand (GITRL) to GITR and inducible co-stimulator (ICOS) ligand (ICOSL) to ICOS. Th2 activation induces anti-inflammatory M2 macrophages, together with decreased Th17 responses promote resolution of synovitis. In contrast, ILC1s and ILC3s were differentiated under stimulation of IL-12, IL-15, IL-18, and IL-23, respectively, which further cause Th1 and Th17 activation, proinflammatory M1 macrophage induction, and aggravate inflammation in the joint

Fig. 2

The role of ILC3s in SpA. The intestinal mucosa harbors abundant NCR⁺α4β7⁺ILC3s in homeostatic conditions. In inflammatory settings like SpA, NCR⁺α4β7⁺ILC3s expanded and emigrated from gut into circulation and α4β7-ligand expressing synovial tissue via chemokine like CCL20, where they produce inflammatory cytokines such as IL-17, IL-22, and GM-CSF to promote local joint inflammation. In the meantime, ILC3s might acquire ILC1-like properties under stimulation of IL-12