Immunomodulatory roles of CTRP3 in endotoxemia and metabolic stress

Abstract

C1q/TNF‐related protein 3 (CTRP3) is a secreted hormone that modulates hepatic glucose and lipid metabolism. Its circulating levels are reduced in human and rodent models of obesity, a metabolic state accompanied by chronic low‐grade inflammation. Recent studies have demonstrated an anti‐inflammatory role for recombinant CTRP3 in attenuating LPS‐induced systemic inflammation, and its deficiency markedly exacerbates inflammation in a mouse model of rheumatoid arthritis. We used genetic mouse models to explore the immunomodulatory function of CTRP3 in response to acute (LPS challenge) and chronic (high‐fat diet) inflammatory stimuli. In a sublethal dose of LPS challenge, neither CTRP3 deficiency nor its overexpression in transgenic mice had an impact on IL‐1β, IL‐6, TNF‐α, or MIP‐2 induction at the serum protein or mRNA levels, contrary to previous findings based on recombinant CTRP3 administration. In a metabolic context, we measured 71 serum cytokine levels in wild‐type and CTRP3 transgenic mice fed a high‐fat diet or a matched control low‐fat diet. On a low‐fat diet, CTRP3 transgenic mice had elevated circulating levels of multiple chemokines (CCL11, CXCL9, CXCL10, CCL17, CX3CL1, CCL22 and sCD30). However, when obesity was induced with a high‐fat diet, CTRP3 transgenic mice had lower circulating levels of IL‐5, TNF‐α, sVEGF2, and sVEGFR3, and a higher level of soluble gp130. Contingent upon the metabolic state, CTRP3 overexpression altered chemokine levels in lean mice, and attenuated systemic inflammation in the setting of obesity and insulin resistance. These results highlight a context‐dependent immunomodulatory role for CTRP3.

Association of C1q/TNF-Related Protein-3 (CTRP3) and CTRP13 Serum Levels with Coronary Artery Disease in Subjects with and without Type 2 Diabetes Mellitus

“…Specifically, CTRP3 is an anti-inflammatory adipokine which inhibits toll-like receptor (TLR) and nuclear factor κB (NF-κB) signaling pathway and also reduces IL-6 and TNF-α secretion [29,30]. Also, Peterson et al have shown an immunomodulatory role for CTRP3 in systemic and chronic inflammation associated with insulin resistance and obesity, but no role in antagonizing LPS induced inflammation in mice model [31]. A more recent study reported a decrease in CTRP3 serum levels in stable and unstable angina pectoris patients [32].…”

“…Independent association between CTRP3 and CAD can be explained by the effect of CTRP3 on different aspects of atherosclerosis, such as inflammation and metabolic disorders. However, we found no correlation between CTRP3 and inflammatory markers, but association between CTRP3 and CAD may be justified by potent anti-inflammatory effect of CTRP3 on inhibiting inflammatory signaling pathways, reducing secretion of inflammatory mediators [29,37] and its favorable role in systemic and chronic inflammation associated with insulin resistance and obesity [31], as well as, cardio-protective effects of CTRP3 [10]. …”

C1q/TNF‐Related Protein 3 (CTRP3) Function and Regulation

“…The adipose tissue immune response plays amajor role in the development of the chronic proinflammatory state (22, 26). Whereas, CTRP3 is a potential anti-inflammatory mediator, and is negatively associated with the proinflammatory cytokines TNF, IL-6, and C-reactive protein (5, 11, 12, 14, 48, 50, 52, 65, 83). In animal models, diet-induced obesity results in decreased CTRP3 levels concurrent with an elevation in TNF and IL-6 (50).…”

“…Combined, these data show promise for the use of CTRP3 and CTRP3-mediated pathways as a potential anti-inflammatory mediator. However, neither chronic CTRP3 deficiency nor overexpression altered the inflammatory response to a sublethal challenge to LPS (48), indicating that CTRP3 levels need to be regulated transiently to demonstrate an anti-inflammatory effect. Regardless, the potential use of CTRP3 as an inhibitor of inflammation needs to be examined in more detail.…”

Adipose tissue-derived cytokines, CTRPs as biomarkers and therapeutic targets in metabolism and the cardiovascular system

“…Regulates glucose and lipid metabolism regulates systemic inflammation in obesity and insulin resistance; modulates mitochondrial biogenesis; attenuate liver fibrosis; biomarker for diabetic retinopathy; negative regulator of osteoclastogenesis; independent predictor for atherosclerosis [47,[56][57][58][59][60] 4 Hepatic cells Modulates energy metabolism; novel nutrient-responsive central regulator of food intake and energy balance; reduces colitis; suppresses the pyroptosis of trophoblasts derived from rats with preeclampsia [61][62][63] 5 Adipose tissue, ocular tissue…”