Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity

Abstract

While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.

Keywords: osteoclast; rheumatoid arthritis; type 2 immunity; type 2 innate lymphoid cells.

Figure 1

Regulation of inflammation and bone metabolism by type 2 immunity. In an inflammatory status of RA, ILC2s, Th2 cells, and eosinophils exert anti-inflammatory properties in the inflamed joint by producing type 2 cytokines such as IL-4 and IL-13. Type 2 cytokines suppress the production of inflammatory cytokines by macrophages. Activated macrophages secrete proinflammatory cytokines IL-1 and TNFα, which stimulate synovial fibroblasts to express RANKL. Type 2 immunity can modulate bone metabolism by regulating the secretion of inflammatory cytokines. In the bone marrow environment, osteoclasts and osteoblasts regulate bone metabolism. IL-4 and IL-13, which are secreted by type 2 immune cells, control osteoclast differentiation directly and indirectly.

Figure 2

Type 2 immunity and cytokine production. Th2 cells, ILC2s, eosinophils, mast cells, basophils, and Th9 cells are type 2 immune cells producing IL-4, IL-5, IL-9, and IL-13.

Figure 3

Type 2 immunity and arthritis. Naive T cells differentiate into Th2 cells by the activation of GATA3 genes. Th2 cells and ILC2s produce IL-4 and IL-13, which suppress macrophage activation in the inflammatory status. Th2 cells and ILC2s also secrete IL-5, activating eosinophils to generate IL-4 and IL-13. Naive T cell-derived Th2 and Th9 can produce IL-9. IL-9 enhances the interaction of ILC2s and Tregs to alleviate inflammation. ILC2s regulate both the initiation and resolution of arthritis.

Figure 4

Type 2 immunity and bone homeostasis. Th2 cells and ILC2s generate IL-4, IL-5, and IL-13. IL-5 activates eosinophil, and it secretes IL-4 and IL-13. Type 2 cytokines suppress the differentiation of osteoclasts by regulating the expression of STAT6. Type 2 cytokines stimulate osteoblasts to generate OPG, which inhibits osteoclastogenesis.