The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPAR??

Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate pro-inflammatory (M1) versus pro-healing (M2) macrophages activation. Here, we observed that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) -deleted macrophages exhibited enhanced M1 phenotype and promoted DSS induced colitis development. However, the IGF2BP2-/- macrophages were refractory to IL4 induced activation and alleviated cockroach extract induced pulmonary allergic inflammation. Molecular studies indicated IGF2BP2 switched M1 macrophages to M2 activation by targeting tuberous sclerosis 1 (TSC1) via an N6-methyladenosine-dependent manner. Additionally, we also showed a signal transducer and activators of transcription 6 (STAT6) - high mobility group AT-hook 2 (HMGA2) -IGF2BP2-peroxisome proliferator activated receptor-? (PPAR?) axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases. Overall design: IRIP-seq analysis of IGF2BP2 versus input in BMDMs