Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond

Abstract

Obesity-associated inflammation stems from a combination of cell-intrinsic changes of individual immune cell subsets and the dynamic crosstalk amongst a broad array of immune cells. Although much of the focus of immune cell contributions to metabolic disease has focused on adipose tissue-associated cells, these potent sources of inflammation inhabit other metabolic regulatory tissues, including liver and gut, and recirculate to promote systemic inflammation and thus obesity comorbidities. Tissue-associated immune cells, especially T cell subpopulations, have become a hotspot of inquiry based on their contributions to obesity, type 2 diabetes, non-alcoholic fatty liver diseases and certain types of cancers. The cell-cell interactions that take place under the stress of obesity are mediated by intracellular contact and cytokine production, and constitute a complicated network that drives the phenotypic alterations of immune cells and perpetuates a feed-forward loop of metabolic decline. Herein we discuss immune cell functions in various tissues and obesity-associated cancers from the viewpoint of inflammation. We also emphasize recent advances in the understanding of crosstalk amongst immune cell subsets under obese conditions, and suggest future directions for focused investigations with clinical relevance.

Keywords: cancer; crosstalk; inflammation; obesity; tissue-specific T cells.

Figure 1

Immune cells interaction in adipose tissue in obesity. Obese AT shifts macrophage polarization to the M1 phenotype (F4/80⁺), macrophages recruit CD4⁺ T cell by producing RANTES which is the ligand of CCR5 expressed on T cells. With the stimulation of fate specifying cytokines, CD4⁺ T cells differentiate into different effectors including Th1, Th2, Th17, and Treg cells. CD11c⁺ DCs secret IL-12 and IL-18 which further polarize CD4⁺ T cells to Th1 cells in AT. Th1 cells interact with adipocytes through MHC Class II molecules suppressing AT IL-33 production from unspecified cellular sources, which promotes Treg proliferation. Adipocytes also communicate with iNKT cells via CD1d molecules expressed on adipocytes inducing iNKT cells to produce IL-2 and other cytokines that generally counter AT inflammation. B cells and Th17 interaction is also likely mediated by MHC Class II molecules and costimulatory receptors, which facilitates IL-17 and IL-22 production. During obesity, AT Th2 and Treg populations decline, and the balance is thus skewed to pro-inflammatory with increased Th1 and Th17 populations. Typical pro-inflammatory T cells in AT are colored blue, and anti-inflammatory T cells in AT are colored pink.

Figure 2

Immune cells in obesity-associated cancers. Obese AT adjacent to cancer sites generates IL-6 and TNF-α, which are inflammatory initiators of tumor cell migration in different tissues/organs. Tregs are present at tumor microenvironment in liver, gut, stomach and esophagus. In liver, IL-6 and TNF-α increase to promote cancer cell proliferation, which in turn recruits CD4⁺ and CD8⁺ T cells to the tumor microenvironment. CD4⁺ T cells produce IL-17 and both CD4⁺ and CD8⁺ T cells produce TNF-α, which further augment the inflammation in liver and aggravate HCC. In colitis, IL-6 regulates intestinal macrophages (Mϕ) polarization to M2-like phenotypes (M2-Mϕ) that produce CCL-20 and recruit CCR6-expressing B cells to the tumor microenvironment. B1 B cells can also polarize macrophages by generating IL-10 in response to the alterations in gut microbiota. CCR6-expressing γδ T cells produce IL-17, which promotes colonic inflammation and deteriorates colorectal cancer. Omentum-derived CD8⁺ T cells are enriched in the stomach and esophageal tumor microenvironment, and Th17 responses are triggered in the presence of Helicobacter felis in stomach.