| dc.description.abstract | Under obese stress, adipose tissue macrophages (ATMs) undergo a phenotypic switch from anti-inflammatory status (M2) to proinflammatory (M1) status, a major contributor to the development of chronic tissue inflammation and insulin resistance which are causal factors for type II diabetes. However, the mechanisms underlying the control of macrophage activation statuses have not been fully elucidated. In this study, we demonstrate that interferon regulatory factor 6 (IRF6) exerts a profound impact on macrophage polarization.
Interestingly, we observed that the expression of IRF6 was dramatically suppressed in M2 macrophages upon IL4 stimulation, but not in LPS-activated M1 macrophages, as compared to naive (M0) macrophages. In addition, IRF6 expression differs distinctly between lean and obese ATMs. We further investigated the role of IRF6 using gain and loss of function strategies in a well-defined in vitro system. Knockdown of IRF6 with a gene-specific shRNA successfully suppressed IRF6 expression level in macrophages. Interestingly, significantly enhanced M2 responses were demonstrated by elevated levels of the activation-related cell surface markers CD69 and CD86 and the expression of M2-related genes including IRF4, PPARγ, Arginase1, and IL10. Conversely, bone marrow derived macrophages (BMDMs) with ectopic expression of IRF6 displayed blunted M2 responses in the presence of IL4, compared to the M2 BMDMs transfected with an empty vector. In addition, the gain or loss of IRF6 expression did not significantly affect M1 responses of BMDMs upon LPS stimulation, suggesting the regulatory effect of IRF6 primarily acts on enhancing macrophage alternative activation.
In summary, our findings identified a novel transcription factor, IRF6, in mediating macrophage alternative activation program. Further analysis of IRF6 in controlling ATM activaton in the obese context will provide crucial information to understand the ATM action and their contribution to adipose tissue function and subsequent obesity-induced chronic inflammation and insulin resistance. | en |
