The role of infiltrating immune cells in dysfunctional adipose tissue

Abstract

Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases. It is characterized by chronic low-grade inflammation and is observed in obesity, metabolic disorders such as insulin resistance and diabetes. While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFα, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT. These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes. Immune composition varies, depending on the stage and the type of pathology. Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity. The presence of inflammatory cells in AT affects adjacent tissues and organs. In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability. Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity. Anti-inflammatory and protective adiponectin is reduced. AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases. Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target.

Keywords: Adipose tissue; Atherosclerosis; Diabetes; Hypertension; Inflammation.

Figure 1

Triple functions of adipose tissue (VAT/pVAT) in health, obesity and in cardiovascular (CV) disease without obesity. AT compartments differ in characteristics of infiltrating immune cells, characteristics of adipocytes and adipokine profile. In health, protective adipokines and cytokines are important in maintaining vascular homeostasis. In obesity, enlarged adipocytes produce leptin and do not release adiponectin and enhance M1 macrophage accumulation in crown-like structures as well as T effector cells. In CVD without obesity macrophages are atypical, adipocytes are synthetic and create microenvironment for development of TLOs and immune cell activation.

Figure 2

Interactions between adipocytes and immune cells at different stages of metabolic and cardiovascular disease. Interactions involve important immunometabolic regulation.

Figure 3

Perivascular AT inflammation as a mechanism of endothelial dysfunction.