Accumulation of CD11c+CD163+ Adipose Tissue Macrophages through Upregulation of Intracellular 11β-HSD1 in Human Obesity

Abstract

Adipose tissue (AT) macrophages (ATMs) are key players for regulation of AT homeostasis and obesity-related metabolic disorders. However, the phenotypes of human ATMs and regulatory mechanisms of their polarization have not been clearly described. In this study, we investigated human ATMs in both abdominal visceral AT and s.c. AT and proposed an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-glucocorticoid receptor regulatory axis that might dictate M1/M2 polarization in ATMs. The accumulation of CD11cCD163 ATMs in both visceral AT and s.c. AT of obese individuals was confirmed at the cellular level and was found to be clearly correlated with body mass index and production of reactive oxygen species. Using our in vitro system where human peripheral blood monocytes (hPBMs) were cocultured with Simpson-Golabi-Behmel syndrome adipocytes, M1/M2 polarization was found to be dependent on 11β-HSD1, an intracellular glucocorticoid reactivating enzyme. Exposure of hPBMs to cortisol-induced expression of CD163 and RU-486, a glucocorticoid receptor antagonist, significantly abrogated CD163 expression through coculture of mature adipocytes with hPBMs. Moreover, 11β-HSD1 was expressed in crown ATMs in obese AT. Importantly, conditioned medium from coculture of adipocytes with hPBMs enhanced proliferation of human breast cancer MCF7 and MDA-MB-231 cells. In summary, the phenotypic switch of ATMs from M2 to mixed M1/M2 phenotype occurred through differentiation of adipocytes in obese individuals, and upregulation of intracellular 11β-HSD1 might play a role in the process.

Contribution of Adipose Tissue to Development of Cancer

“…For example, in human abdominal subcutaneous adipose, ATMs accumulating in CLS expressed both CD11c and the commonly used M2 marker mannose receptor C type 1 (CD206), as well as both pro- and anti-inflammatory interleukins (IL-1β, IL-6, IL-8, and IL-10) (433). These results are further supported by Nakajima et al, who reported accumulation of ATMs expressing both CD11c and CD163, the latter of which is commonly associated with M2-like macrophages, in abdominal visceral and subcutaneous adipose of obese subjects (269). Shaul et al (350) also described a mixed M1/M2 phenotype in obese murine CD11c+ visceral ATMs, suggesting phenotypic and functional similarities between murine and human ATMs in obesity.…”

Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

“…Early characterization of adipose tissue MF populations first described the obesity-induced appearance of proinflammatory MFs in conjunction with elevated levels of proinflammatory cytokines and chemokines such as TNF-a, IL6, and CCL2 (99,100). However, recent extensive profiling of adipose tissue MFs from adipose tissue of obese mice and humans has revealed a "mixed" pro-and anti-inflammatory phenotype (101)(102)(103)(104)(105)(106). Considering the complexity of phenotyping MFs by surface markers and expression profiling, the contribution of underlying metabolic parameters has the potential to inform us about MF phenotype and function in adipose tissue of obese individuals.…”

Properties and functions of adipose tissue macrophages in obesity

“…48 Interestingly, also CD11c + CD163 + ATMs were found to accumulate in fat of obese individuals and correlate with high BMI as well as the production of reactive oxygen species. 49 In addition to CD11c + CD206 + ATMs, it has been indicated that the population of CD11c + CD64 + ATMs also defines pro-inflammatory macrophages. 38 Additionally, the population of CD14 + CD16 + CD36 high ATMs has been shown to include highly phagocytic macrophages.…”