Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease

Abstract

Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, caloric restriction, or exercise training.

Keywords: Adipose tissue; Chronic inflammation; Endothelium; Hypoxia; Innate immune cells; Obesity; Physical exercise.

Fig. 1

ATM accumulation through proliferation, recruitment, and retention. Macrophages accumulate in the adipose tissue through cell division, recruitment and retention. Recruitment can be driven by MCP-1 [112, 117]. Local proliferation occurs especially in the early stage of obesity [111, 113, 114] and is induced by IL-4, IL-6 and MCP-1 [111, 113, 128]. Retention is mediated by direct adhesion of macrophages to adipocytes through the interaction of α4 on macrophages with VCAM-1 on adipocytes [115, 116] and netrin-1, the expression of which is induced in macrophages by palmitate [115]. ATM, adipose tissue macrophage; MCP-1, monocyte chemoattractant protein 1; IL, interleukin; VCAM-1, vascular cell adhesion molecule-1.

Fig. 2

Innate immune cells in the lean and obese adipose tissue. The lean adipose tissue predominantly contains non-inflammatory cells, including alternatively activated (M2-like) macrophages, eosinophils, regulatory T cells and ILC2 cells, and type 2 cytokines, such as IL-4, IL-13, IL-5 and IL-33 [2, 54, 55, 56, 57, 58, 59, 60]. ILC2 are maintained in the adipose tissue by IL-33 and IL-25 [56, 58, 59, 60, 215] and produce IL-5, which is a key cytokine for maintenance of eosinophil and consequently M2-like macrophage populations [54, 56, 57, 59]. ILC2 also produce IL-13, which induces macrophage alternative activation [215]. Moreover, they secrete methionine-encephalin, which promotes adipose tissue thermogenesis (beiging) [60]. Eosinophils are a major cell source of IL-4 in the adipose tissue [57]. IL-4 maintains M2-like macrophages through STAT6 signaling and attenuates adipocyte hypertrophy [55, 56, 57]. IL-6 upregulates the expression of the IL-4 receptor, thereby supporting macrophage alternative activation [128, 171]. Adipokines, such as adiponectin, omentin, CTRPs and SFRP5, and sphingolipids also have anti-inflammatory effects [47, 179]. Hallmarks of M2-like ATM are KLF4, arginase 1, Retnla and Chi3l3 and GPS2 expression [170, 174]. In obesity, the immune profile of the adipose tissue shifts to a pro-inflammatory state through recruitment of macrophages, neutrophils and NK cells [5, 6, 26, 28, 68, 69, 70, 71]. Adipocyte-derived pro-inflammatory factors, such as MCP-1, IL-6, TNF and leptin, chemerin and resistin, stimulate activation and recruitment of immune cells [6, 20, 42, 43, 44, 45, 47, 72, 73, 74, 75, 76]. Extracellular matrix components, such as versican and biglycan derived from adipocytes and macrophages, respectively, promote macrophage pro-inflammatory activation [143, 144]. NCR1 ligation on NK cells triggers IFN-γ release, which also instigates macrophage activation [71]. Macrophages are retained in the adipose tissue through the interaction of α4 with VCAM-1 [116]. Pro-inflammatory macrophages are featured by increased expression of TNF, IL-6, iNOS, inflammasome activation, IL-1β production, and enhanced ER stress [68, 132, 133, 134, 135, 136, 149, 150, 151, 152, 153, 154, 156, 157, 158, 159, 163, 164]. Macrophages within crown-like structures surrounding dying adipocytes are CD9⁺, highly phagocytic, lipid-laden, Trem2⁺ and can form multinucleated giant cells through cell fusion [76, 181, 191, 193]. ATMs outside of crown-like structures are pro-inflammatory and marked by CD11c [191]. Pro-inflammatory macrophages via IL-1β and neutrophils through elastase perpetuate insulin resistance [69, 149, 150, 151, 152, 153, 154, 159, 166, 167, 230]. In contrast, PAHSA, DHA, and EPA decrease macrophage-mediated adipose tissue inflammation and promote insulin sensitivity [187, 188]. IL, interleukin; ILC, innate lymphoid cell; CTRP, C1q/TNF-related protein; NK, natural killer; MCP-1, monocyte chemoattractant protein 1; SFRP5, secreted frizzled-related protein 5; VCAM-1, vascular cell adhesion molecule-1; TNF, tumor necrosis factor; iNOS, inducible nitric oxide synthase; ATM, adipose tissue macrophage; KLF4, Krüppel-like factor 4; GPS2, G protein pathway suppressor 2; ER, endoplasmic reticulum; Trem2, triggering receptor expressed on myeloid cells 2; PAHSA, palmitic acid-9-hydroxystearic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.