Impact of CCL2 and CCR2 chemokine/receptor deficiencies on macrophage recruitment and continuous glucose monitoring in vivo

Abstract

The accumulation of macrophages (MΦ) at the sensor-tissue interface is thought to be a major player in controlling tissue reactions and sensor performance in vivo. Nevertheless until recently no direct demonstration of the causal relationship between MΦ aggregation and loss of sensor function existed. Using a Continuous Glucose Monitoring (CGM) murine model we previously demonstrated that genetic deficiencies of MΦ or depletion of MΦ decreased MΦ accumulation at sensor implantation sites, which led to significantly enhanced CGM performance, when compared to normal mice. Additional studies in our laboratories have also demonstrated that MΦ can act as “metabolic sinks” by depleting glucose levels at the implanted sensors in vitro and in vivo. In the present study we extended these observations by demonstrating that MΦ chemokine (CCL2) and receptor (CCR2) knockout mice displayed a decrease in inflammation and MΦ recruitment at sensor implantation sites, when compared to normal mice. This decreased MΦ recruitment significantly enhanced CGM performance when compared to control mice. These studies demonstrated the importance of the CCL2 family of chemokines and related receptors in MΦ recruitment and sensor performance and suggest chemokine targets for enhancing CGM in vivo.

Epac ameliorates tubulointerstitial inflammation in diabetic nephropathy via C/EBPβ/SOCS3/STAT3 pathway

“…Pharmacologic inhibition of MCP-1 or CCR2 effectively reduced the recruitment of macrophage into the interstitial compartment and improved tubulointerstitial damage (41,42).In diabetic animal models treated with STZ, deficiency of MCP-1 decreased the number of macrophage accumulation and prevented early diabetic renal injury (34,40). In agreement with these previous studies, we observed that upregulated renal MCP-1 expression was accompanied by increased macrophage infiltration in tubular interstitial in diabetic mice.…”

“…MCP-1, a member of the CC chemokine family acting through its receptor CCR2 (38), is a critical factor in recruiting monocytes/macrophages into inflammation site (39). The expression of MCP-1 in tubular cells and urinary excretion of the protein were both upregulated in human and experimental diabetes, which coincided with macrophage infiltration in both glomeruli and interstitial and correlated with levels of albuminuria and renal function decline (34,37,39,40).…”

Obesity: An Immunometabolic Perspective

“…Increased OSM contributes to hepatic IR and the development of NASH (46). High levels of TNF-α released by M1-KCs stimulates hepatic expression of CCL2, a powerful monocyte chemoattractant, which recruits CCR2 + Ly6C high monocytes from the vasculature into the liver (47), where they differentiate into Ly6C high macrophages. The Ly6C high macrophages amplify the severity of obesity-induced inflammation and hepatic IR through secretion of TNF-α and IL-6 (48).…”

Distinct Hepatic Macrophage Populations in Lean and Obese Mice

“…Increased OSM contributes to hepatic IR and the development of non-alcoholic steato hepatitis (NASH) (71). High levels of TNF-α released by M1-KCs stimulate hepatic expression of CCL2 (also known as MCP1), a powerful monocyte chemoattractant, which recruits CCR2 + Ly6C high monocytes from the vasculature into the liver (72), where they differentiate into Ly6C high macrophages. The Ly6C high macrophages amplify the severity of obesity-induced inflammation and hepatic IR through the secretion of TNF-α and interleukin 6 (IL-6) (12).…”