IRF6 Regulates Alternative Activation by Suppressing PPARγ in Male Murine Macrophages

Aberrant proinflammatory and suppressed anti-inflammatory (alternative; M2) macrophage activation underlies the chronic inflammation associated with obesity and other metabolic disorders. This study demonstrates a critical role for interferon regulatory factor 6 (IRF6) in regulating macrophage M2 activation by suppressing peroxisome proliferator-activated receptor-gamma (PPAR gamma) expression, a critical regulator of alternative macrophage polarization. The data demonstrate suppression of IRF6 in both M2 macrophages and obese adipose tissue macrophages. Using gainand loss-of-function strategies, we confirmed that IRF6 knockdown enhanced M2 activation, whereas IRF6 overexpression dramatically attenuated M2 activation. Computational target prediction analysis coupled with chromatin immunoprecipitation indicated that IRF6 suppresses PPAR gamma through binding IRF recognition sites located upstream of the PPARg coding region. Taken together, our results suggest that an IRF6/PPAR gamma regulatory axis suppresses anti-inflammatory responses in bone marrow-derived macrophages and provides references for future study addressing dysregulated metabolic and immunologic homeostasis of obese adipose tissue.