Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

Abstract

Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

“…Using flow cytometry coupled with single-cell RNA sequencing (scRNA-seq) followed by imaging, Lazar et al identified CD11b+Ly6c-CD9-ATMs to be interstitially spaced, while CD11b+Ly6c-CD9+ ATMs were within crown-like structures and increased with obesity-this was true in both mouse and human AT. 37 The CD9+ ATMs expressed genes related to lipid metabolism (including Lpl, Plin2, Cd63), lysosomal pathways (Acp5, Ctss, Lamp2, Lipa), As expected, the largest changes were an expansion of ATMs and a reduction in T regulatory cells and type 2 innate lymphoid cells. Importantly, ATMs from leptin-deficient obese mice fed a chow diet also showed these changes.…”

Properties and functions of adipose tissue macrophages in obesity

“…Due to its expression on dendritic cells (DCs), a question in the field has been the ability to differentiate ATMs from adipose tissue dendritic cells (ATDCs) given that F4/80 and CD11b are also found on ATDCs. 40 Thus far, Ly6c + (recruited subset), Ly6c À CD9 + (pro-inflammatory subset) and Ly6c À CD9 À (anti-inflammatory subset) shared distinct tissue localization, and Ly6c À CD9 + were also identified in human AT. 39 While a CD11c-based scheme differentiates ATM subsets in mice and humans, recent transcriptomic studies suggest a revision to this scheme.…”

“…The Ly6c À CD9 + population was described as the subset that accumulated with obesity specifically within the CLSs, had high amounts of intracellular lipid in lysosome-like structures, expressed genes related to lysosomal-dependent lipid metabolism, secreted exosome-size vesicles, and had gene expression and regulatory profiles enriched for pro-inflammatory genes. 40 Thus far, Ly6c + (recruited subset), Ly6c À CD9 + (pro-inflammatory subset) and Ly6c À CD9 À (anti-inflammatory subset) shared distinct tissue localization, and Ly6c À CD9 + were also identified in human AT. The authors note a lack of differential expression of CD11c in these populations, so future studies will need to clarify the functional role of CD9 in ATMs as well as other AT stromal cells.…”

An update on immune dysregulation in obesity‐related insulin resistance

“…The phenotypic switch from M2 to M1 like that occurs during obesity is mainly attributed to the recruitment of monocyte to the AT and not conversion of tissue‐resident M2‐like macrophages . In obese animals, ATMs residing outside of CLS are adipogenic Ly6c + while those in the CLS are predominantly CD9 + that phagocytose the residual lipid droplets and produce pro‐inflammatory cytokines . CD9 + macrophages are most similar to the CD11c + macrophages and their adoptive transfer into lean mice activates gene expression profiles related to obesity within the AT .…”

“…In obese animals, ATMs residing outside of CLS are adipogenic Ly6c + while those in the CLS are predominantly CD9 + that phagocytose the residual lipid droplets and produce pro‐inflammatory cytokines . CD9 + macrophages are most similar to the CD11c + macrophages and their adoptive transfer into lean mice activates gene expression profiles related to obesity within the AT . Deletion of CD11c, MHC‐II, TNF‐ɑ, CCR2 and CD74 genes before HFD fed in mice causes a marked local and systemic decrease in inflammatory markers and improved glucose tolerance …”