Fat gets picky with macrophages

Three studies published in The Journal of Clinical Investigation show that in mouse models of atherosclerosis and obesity distinct subsets of monocytes are recruited, different chemokine receptors are used and a phenotypic switch in macrophage differentiation occurs at sites of lipid accumulation. These studies provide new insights into the heterogeneity of monocyte recruitment and macrophage phenotype in lipid-rich tissues.

Atherosclerosis is an inflammatory disease that involves the accumulation of lipids and macrophages and the formation of plaques in the arteries. Mouse monocytes, the precursors of macrophages, can be divided into two main subsets on the basis of their expression of receptors that include Ly6C, GR1, CC-chemokine receptor 2 (CCR2) and CX₃C-chemokine receptor 1 (CX₃CR1). Ly6C^hi monocytes (sometimes referred to as inflammatory monocytes) are GR1⁺CCR2⁺CX₃CR1^low, whereas Ly6C^lowmonocytes are GR1⁻CCR2⁻CX₃CR1^hi. But what role do these circulating monocyte subsets have in the development of atherosclerosis?

Both Swirski et al. and Tacke et al. examined the repertoire of monocytes in apolipoprotein E (APOE)-deficient mice that were fed a high-fat diet — a mouse model of atherosclerosis. They found that the Ly6C^hi monocyte subset continuously expanded in the periphery compared with Ly6C^low monocytes. Interestingly, Ly6C^hi monocytes were shown to efficiently accumulate in atherosclerotic lesions and Swirski et al. further showed that these cells differentiated into lesional macrophages.

Owing to the differential expression of chemokine receptors by these monocyte subsets, Tacke et al. examined the role of the individual receptors in the accumulation of monocytes in atherosclerotic plaques. They found that the inflammatory Ly6C^hi monocytes used CX₃CR1 (as well as CCR2 and CCR5) to enter the plaques. Ly6C^low monocytes could also enter atherosclerotic plaques, albeit less frequently. But unlike Ly6C^hi monocytes, Ly6C^low monocytes entered the plaques in a CCR2- and CX₃CR1-independent, CCR5-dependent manner and were more likely to become CD11c⁺ dendritic-cell-like cells.

Lumeng et al. examined the phenotype of macrophages that migrate to adipose tissue in diet-induced obese mice compared with those in lean mice that were fed a normal diet. Macrophages isolated from adipose tissue from lean mice expressed many hallmarks of alternatively activated macrophages — that is, they expressed genes encoding the anti-inflammatory molecules interleukin-10 (IL-10) and IL-1 decoy receptor. By contrast, adipose-tissue macrophages from obese mice undergo a phenotypic switch to express pro-inflammatory molecules, such as tumour-necrosis factor (TNF) and inducible nitric-oxide synthase (iNOS). Interestingly, macrophages from CCR2-deficient obese mice expressed alternatively activated macrophage markers at levels similar to macrophages from lean mice. This indicates that, in the absence of CCR2-dependent recruitment, adipose-tissue macrophages might have reduced inflammatory capacity.

Collectively, these studies highlight potential targets to suppress the inflammatory response associated with lipid-associated diseases, such as obesity and atherosclerosis.