Critical role of the C5a-activated neutrophils in high-fat diet-induced vascular inflammation

Abstract

Exceed and chronic high-fat diet (HFD) contributes to the diagnosis and development of atherosclerosis, obesity, and metabolic syndrome. However, the key molecular component(s) triggered by HFD responsible for initiating vascular inflammation remain unknown. We observed that feeding HFD for 4 weeks is sufficient to induce leukocyte recruitment in the femoral artery of wild-type mice. Neutrophil- and monocyte-depletion analyses confirmed the preferential recruitment of neutrophils in these mice. Protein analysis of sera from HFD-fed mice revealed a marked elevation of complement component C5a levels. Exogenous C5a alone induced leukocyte recruitment, which was abolished by a C5a-receptor antagonist. We also examined the role of neutrophil-derived MCP-1 in accumulation of leukocytes in the artery. These results demonstrated a previously unrecognized role for C5a and neutrophils in the early onset of HFD-induced vascular inflammation. Further study may help in elucidating a novel regulatory pathway to control diet-induced inflammation such as that in case of atherosclerosis.

Dysfunctional adipose tissue and low-grade inflammation in the management of the metabolic syndrome: current practices and future advances

“…Other aspects of the complement system with potential relevance in adipose-tissue-mediated inflammation and insulin resistance include the terminal pathway of complement activation, which leads to the generation of the proinflammatory anaphylatoxin C5a and the (sub)lytic terminal complement complex (TCC, also known as C5b-9). In human cohorts and in animal studies, C5a and TCC were associated with low-grade inflammation 65 , 70 , 81 . Notably, the terminal pathway of complement activation has been implicated in the activation of the NLRP3 inflammasome 82 – 84 .…”

“…The complement system has been implicated in cardiometabolic diseases, including the metabolic syndrome 47 , 61 , 62 . Complement activation is strongly associated with low-grade inflammation in the metabolic syndrome and related cardiometabolic diseases 63 – 70 . Notably, we have shown in observational studies in humans that activated complement factors are strongly associated with markers of endothelial dysfunction 64 , 65 , which are thought to reflect mainly greater microvascular endothelial dysfunction 10 .…”

Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

“…To assess this potential action, we measured plasma levels of inflammatory markers pathologically altered during obesity. Treatment of DIO mice with GLP-1/Dexa induced a prominent reduction in chemotactic peptides linked to high-fat-diet-induced vascular inflammation, such as the complement component C5a (Osaka et al, 2016) and soluble intercellular adhesion molecule-1 sICAM1 (Shai et al, 2006). The conjugate reduced plasma levels of cytokines involved in T cell recruitment, insulin resistance, and diabetes, including the chemokine (C-X-C motif) ligands CXCL1, CXCL10, and interleukin 16 (Dufour et al, 2002;Kim et al, 2014a;Meagher et al, 2010) (Figures 5E and S7F).…”

The importance of hemogram parameters in family medicine for coronary artery disease

“…The chronic inflammatory response is a critical element in the pathogenesis of atherosclerosis [9] , which is associated with the production of platelets and lymphocytes. MPV, NLR, and PLR are simple, inexpensive, and easily obtained parameters using hemogram results that can be used as disease activation indicators in inflammatory diseases.…”