Molecular mechanism of crosstalk between immune and metabolic systems in metabolic syndrome

Abstract

Chronic inflammation is currently considered as a molecular basis of metabolic syndrome. Particularly, obesity-induced inflammation in adipose tissue is the origin of chronic inflammation of metabolic syndrome. Adipose tissue contains not only mature adipocytes with large lipid droplets, but also a variety of stromal cells including adipocyte precursors, vascular component cells, immune cells, and fibroblasts. However, crosstalk between those various cell types in adipose tissue in obesity still remains to be fully understood. We focus on two innate immune receptors, Toll-like receptor 4 (TLR4) and macrophage-inducible C-type lectin (Mincle). We provided evidence that adipocyte-derived saturated fatty acids (SFAs) activate macrophage TLR4 signaling pathway, thereby forming a vicious cycle of inflammatory responses during the development of obesity. Intriguingly, the TLR4 signaling pathway is modulated metabolically and epigenetically: SFAs augment TLR4 signaling through the integrated stress response and chromatin remodeling, such as histone methylation, regulates dynamic transcription patterns downstream of TLR4 signaling. Another innate immune receptor Mincle senses cell death, which is a trigger of chronic inflammatory diseases including obesity. Macrophages form a histological structure termed "crown-like structure (CLS)", in which macrophages surround dead adipocytes to engulf cell debris and residual lipids. Mincle is exclusively expressed in macrophages forming the CLS in obese adipose tissue and regulates adipocyte death-triggered adipose tissue fibrosis. In addition to adipose tissue, we found a structure similar to CLS in the liver of nonalcoholic steatohepatitis (NASH) and the kidney after acute kidney injury. This review article highlights the recent progress of the crosstalk between immune and metabolic systems in metabolic syndrome, with a focus on innate immune receptors.

Keywords: Crown-like structure; Fatty acids; Metabolic syndrome; Mincle; Obesity; TLR4.

Fig. 1

Potential mechanism of metabolic and epigenetic regulation of TLR4 signaling. ER is an interface between immune and metabolic systems. PERK and IRE1α, along with their downstream effectors, ATF4 and XBP1, respectively, are involved in SFA-induced metabolic inflammatory responses. TLR4 signal–mediated proinflammatory cytokines are divided into the following two groups. Primary response genes are rapidly upregulated in response to stimuli, while secondary response genes are induced later. Accumulating evidence has highlighted the significant role of chromatin remodeling in the regulation of these upon TLR4 activation. Among others, covalent modifications at histones H3 and H4 have been shown to play a key role in regulating chromatin assembly and the recruitment of inducible transcription factors, suggesting the epigenetic regulation of TLR4 signaling. Created with BioRender.com

Fig. 2

CLS is a hallmark of obesity-induced chronic inflammation. Obesity induces inflammation and fibrosis in adipose tissue and the liver. Chronic inflammation leads to a characteristic histological structure termed “crown-like structure (CLS)” in which macrophages surround dead adipocytes, resulting in fibrosis. An innate immune receptor Mincle functions as a cell death sensor, which is selectively upregulated in the macrophages that constitute CLS in obese adipose tissue. Mincle regulates adipocyte death-triggered fibrogenesis and controls lipid storage function of adipose tissue, thereby affecting ectopic lipid accumulation in remote organs such as the liver. In nonalcoholic steatohepatitis, there is a structure similar to CLS in which macrophages surround dead hepatocytes with excessive lipids. Created with BioRender.com

Fig. 3

An interface between immune and metabolic systems: adipose tissue CLS. Immune cells infiltrate adipose tissue in response to body weight gain, induce chronic inflammation in adipose tissue, and affect the functions of remote organs, such as the liver, through aberrant adipokine production. In this regard, the CLS serves as a driving engine to induce metabolic inflammatory responses in obese adipose tissue (adipose tissue CLS). Intriguingly, a similar structure occurs in the liver in the progression from simple hepatic steatosis to NASH (hepatic CLS). Thus, the considerable attention to the interface between immune and metabolic systems has led to the emerging concept of “immunometabolism.” Created with BioRender.com