Abstract
BACKGROUND: The prevalence of obesity is rising and leads to increased morbidity and mortality. Adipose tissue inflammation, due to accumulation and activation of adipose tissue macrophages (ATMs), is a key driver of this phenomenon. Macrophages are heterogeneous cells, adapting quickly to the microenvironment, resulting in so-called M1 or M2 macrophages. In this study, we describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice. METHODS: LDLR(-/-) mice received a high fat diet (HFD) for 5 weeks or 16 weeks to induce obesity. Adipose tissues were isolated and immune cell subsets were analyzed with flow cytometry or microarray analysis. Bone marrow transplantation (BMT) using CD45.1 and CD45.2 LDLR(-/-) mice was performed to determine ATM origin. RESULTS: Upon HFD, there is a massive increase of ATM subsets in the adipose tissue. CD11c(-)M2 ATMs could be subdivided based on their MHC2 expression into CD11c(-)MHC2(high) ATMs and previously unidentified CD11c(-)MHC2(low) ATMs. CD11c(-)MHC2(low) ATMs accumulated very rapidly after 10 days of HFD, after which they increased even further with prolonged HFD. Microarray data showed that CD11c(-)MHC2(low) ATMs resembled CD11c(-)MHC2(high) ATMs in the steady state, but became more inflammatory during development of obesity. In vitro stimulation of bone marrow-derived macrophages with palmitate, abundantly present in HFD, resulted in the induction of the CD11c(-)MHC2(low) phenotype. CONCLUSIONS: Among M2 macrophages, a novel pro-inflammatory subset of macrophages was found based on their low level of MHC2 expression. This subset may play a role in the development of adipose tissue inflammation.