Macrophages, Meta-Inflammation, and Immuno-Metabolism

Figure 1

Interdependence of adipocyte and macrophage functional modes in the lean and obese states. The left side of the diagram depicts the insulin-sensitive adipocyte and M2-type adipose tissue macrophage characteristic of adipose tissue in the lean state. Adipocytes are of a normal size and are sensitive to insulin’s signal to minimize the cleavage of fatty acids from triglyceride stores (lipolysis). Consequently, local and circulating concentrations of FFA are maintained below harmful levels. Healthy adipocytes (as well as other cell types not shown here) are a source of M2-inducing cytokines—IL-4 and IL-13, which signal through STAT6 phosphorylation to induce transcription of PPARs, their coactivator, PGC-1β, and 12/15-LO. PGC-1β promotes the assembly of the STAT6 transcription complex, thereby amplifying the expression of signature M2 proteins, such as arginase-1 and the pattern recognition/endocytic receptor CD206. Induction of 12/15-LO further enhances the M2 phenotype and insulin sensitivity by synthesizing 15-HETE (from arachidonic acid), 17S-HDHA, and RvD1 (the latter two from DHA). RvD1 is a specialized proresolution mediator and appears to act on its cognate receptor (not shown) expressed on macrophages and adipocytes to promote the M2 phenotype and to induce adiponectin secretion, respectively. Indeed, healthy adipocytes produce and secrete greater amounts of adiponectin than in the obese, and this adipokine exerts insulin sensitizing and anti-inflammatory effects, locally and systemically. Adiponectin signaling inhibits M1-skewing, enhances PPAR-γ activity, and increases oxidative metabolism in adipose tissue macrophages. The ligand binding domain of PPAR-γ recognizes oxygenated metabolites of polyunsaturated fatty acids which are consumed in the context of a healthful diet, including 15-HETE and 17S-HDHA. Activated PPAR-γ inhibits NF-κB-dependent gene expression. It also forms a heterodimer with RXR to induce proteins involved in the uptake (e.g., CD36), esterification (e.g., DGAT), and oxidation (e.g., LCAD) of FFAs released from adjacent adipocytes. Consequently, the concentration of FFAs does not reach toxic levels. Free, extracellular DHA contributes to M2-skewing by activating a novel surface receptor (GRP120). During weight gain, adipocytes undergo hypertrophy in an attempt to store excess FAs as neutral lipids, that is, triglyceride. Unfortunately, the excess supply of FAs eventually surpasses the capacity of adipocytes and adipose tissue to store lipids, leading to an increase in FFA concentrations. The reduced sensitivity to insulin that accompanies obesity also increases FA release by allowing lipolysis of triglycerides. In conjunction with LPS derived from the abnormal intestinal flora that populates the obese, and with M1/Th1-type cytokines, free saturated FAs activate macrophage IKK and JNK1, thereby inducing the M1 immune program. M1 macrophages produce IL-1β and TNFα, which increase and activate adipocyte IKK and JNK to block insulin signaling. As a result, the number of M1 macrophages parallels the expansion of adipose tissue, exacerbating inflammation and insulin resistance.