Macrophage heterogeneity and tissue lipids

Abstract

Macrophages are present as resident cells in adipose tissue, and blood monocytes are recruited in increased numbers to sites of lipid accumulation in atherosclerosis, a modified form of inflammation in the arterial wall. Recent findings reported by 3 separate groups in this issue of the JCI provide evidence for distinct monocyte subsets, differential chemokine receptor usage, and phenotypic modulation of macrophages in murine models of genetic and high-fat diet-induced disease (see the related articles beginning on pages 175, 185, and 195). These studies raise prospects for selective therapeutic targets to ameliorate macrophage hyperinflammatory responses, while sparing host defense and repair mechanisms.

Figure 1. Heterogeneity of monocytes and tissue macrophages.

This schematic summarizes previous evidence for monocytic subsets giving rise to tissue macrophages and myeloid DCs in the absence and presence of microbially elicited inflammation. Two distinct subpopulations of monocytes can be identified in the circulation, CD14⁺CD16⁺ versus CD14⁺⁺CD16^– in the human and Ly-6^lo/Gr-1^lo versus Ly-6^hi/Gr-1^hi in the mouse. There are also differences in expression of CX3CR1 (fractalkine receptor), CCR2, and CD62L (L selectin ligand). Experimental studies in rodents have shown that the CX3CR1^lo subset gives rise to recruited macrophages and DCs, in response to a proinflammatory stimulus, whereas the CX3CR1^lo subset may give rise to resident tissue cells.

Figure 2. Monocyte and macrophage recruitment and response to tissue lipids.

Summary of findings reported in the present studies (–5). It is not clear whether individual monocytes express all markers and whether cells of each subset are recruited stochastically from the circulation. Some markers are not shown, which reflects lack of study rather than absence of expression. See text for role of Gr-1^lo cells in atherosclerosis and in the generation of CD11c^– cells. CCR5 involvement is partial (part; see text).