The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

Abstract

C1q/TNF-related proteins (CTRP) including CTRP3 are a group of secreted proteins which have a complement C1q-like domain in common, and play versatile roles in lipid metabolism, inflammation, tumor metastasis and bone metabolism. Previously, we showed that the expression of C1qtnf3, encoding CTRP3, is highly augmented in joints of autoimmune arthritis models and CTRP3-deficiency exacerbates collagen-induced arthritis in mice. However, the mechanisms how CTRP3-deficiency exacerbates arthritis still remain to be elucidated. In this study, we showed that CTRP3 was highly expressed in Th17 cell, a key player for the development of autoimmune diseases, and Th17 cell differentiation was augmented in C1qtnf3–/– mice. Th17 cell differentiation, but not Th1 cell differentiation, was suppressed by CTRP3 and this suppression was abolished by the treatment with a receptor antagonist against AdipoR2, but not AdipoR1, associated with suppression of Rorc and Stat3 expression. Furthermore, AdipoR1 and AdipoR2 agonist, AdipoRon suppressed Th17 cell differentiation via AdipoR2, but not AdipoR1. The development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis was enhanced in C1qtnf3–/– mice associated with increase of Th17 cell population. CTRP3 inhibited MOG-induced IL-17 production from T cells by affecting both T cells and dendritic cells. These results show that CTRP3 is an endogenous regulator of Th17 differentiation, suggesting that the CTRP3-AdipoR2 axis is a good target for the treatment of Th17 cell-mediated diseases.

CTRP11 contributes modestly to systemic metabolism and energy balance

“…4,5 Within this family, there is a subgroup of 15 proteins referred to as the C1q/ TNF-related proteins (CTRP1-15), 6 which we have initially identified based on shared sequence homology to the insulin-sensitizing hormone, adiponectin. 7,8 Multiple approaches-involving recombinant protein infusion, transgenic overexpression, and knockout mouse modelshave provided critical in vivo evidence for CTRPs in regulating diverse aspects of glucose and lipid metabolism, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] obesity-linked low-grade inflammation, 10,27 as well as other diverse functions in the heart and vasculature, [28][29][30][31][32][33][34] kidney, [35][36][37] muscle and tendon, 38,39 bone, 40 immune system, [41][42][43][44] and the central nervous system. [45][46][47]…”

C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization

“…Our current knowledge about potential C1QTNF3-receptors and downstream signaling pathways is very limited. To date, Lysosomal-associated membrane protein 1, Lysosome membrane protein 2 ( 55 ) and Adiponectin receptor 2 ( 56 ) have been suggested as potential receptors for C1QTNF3 but the significance of these finding are yet largely unknown. However, several studies show that C1QTNF3 activates the MEK/ERK and the PI3K/Akt pathway and its beneficial metabolic and anti-inflammatory effects are thought to primarily depend on the PI3K/Akt pathway ( 26 , 41 , 57 – 59 ).…”

Lonicerae Japonicae Flos extract and chlorogenic acid attenuates high-fat-diet- induced prediabetes via CTRPs-AdipoRs-AMPK/PPARα axes

“…The phosphorylation of AMPK improves hepatic IRS1-PI3K-AKT signaling pathway and increases hepatic insulin sensitivity (30,31). Moreover, AdipoR1 demonstrated as the receptor for CTRP9 (22,23) has been shown to activate the AMPK pathway, whereas AdipoR2 is identified as the receptor for CTRP3 (24) to activate PPARα pathway. In this study, both LJF and CGA increased the expression of AdipoR1 and AdipoR2, and their downstream phosphorylation of AMPK, which may partially account for the beneficial effects of LJF and CGA on lipid and glucose metabolism.…”

“…Clinical and experimental studies have suggested that C1q/TNF-related protein (CTRP) superfamily (including adiponectin, CTRP3, CTRP6, and CTRP9) bind to their receptors AdipoR1 and AdipoR2, could ameliorate impaired glucose tolerance, insulin resistance (IR) via activation of AMPK and PPAR-α pathways, respectively (19,20). Of these, AdipoR1 [identified as the receptor for adiponectin, CTRP6 (21), and CTRP9 (22, 23)] has been shown to activate the AMP-activated protein kinase (AMPK) pathway, and AdipoR2 (identified as the receptor for adiponectin and CTRP3) (24) to activate peroxisome proliferator-activated receptor (PPAR) signaling, thus improving glucose and lipid metabolism and exerting anti-diabetic effects. In addition, the crystal structure of the AdipoRs suggests that AdipoR1 and AdipoR2 possess intrinsic ceramidase activity (25) and promotes desaturase activity (26).…”