] Moreover, m 6A modification exerts its biological functions by “readers”: YTH (YT521‐B homology) domain proteins including YTHDC1–2 and the YTH‐family proteins YTHDF1–3 as well as insulin‐like growth factor 2 mRNA binding proteins IGF2BP1–3. ] m 6A modification is deposited by “writers” the methyltransferase complex containing the methyltransferase‐like 3 and 14 proteins (METT元 and METTL14) and their regulator Wilms tumor 1‐associated protein, and removed by “erasers” demethylases: fat mass and obesity‐associated protein (FTO) and α‐ketoglutarate dependent dioxygenase AlkB homolog 5 (ALKBH5). It is well known that post‐transcriptional modifications of messenger RNAs (mRNAs), among which m 6A is the most abundant internal RNA modification, regulate genes expression by influencing mRNA splicing, stability, translocation and translation. ] While the activation of mTORC1 is relatively well understood at the level of nutrients, growth factors and signal transduction, the post‐transcriptional regulation of the component expression in the mTORC1 pathway remain less clear. ] Activation of mTORC1 accelerates the synthesis of fatty acids and cholesterol though the transcriptional factor peroxisome proliferator activated receptor‐ γ (PPAR γ), which promotes the metabolic reprograming in the anti‐inflammatory macrophages. ] Genetic loss of TSC1 increased proinflammatory response in macrophages while highly resist to IL4 induced M2 polarization. ] The tuberous sclerosis (TSC) complex comprising TSC1 and TSC2 inhibits Rheb small GTPase directly, and Rheb is the upstream of the rapamycin‐sensitive complex 1 (mTORC1), thus to downregulate mTORC1 activity. The mammalian target of rapamycin (mTOR) signaling pathway senses both intracellular and extracellular signals and serves as a regulator of the fate of immune cell populations. ] the intrinsic regulators, which shapes macrophage phenotype, have not been well investigated. ] Although extracellular signals that induce macrophage polarization are well recognized, [ ] In tumors, the tumor associated macrophages (TAMs), which are usually triggered by environmental cues to exhibit an M2 similar phenotype, contribute to build an immunosuppressive tumor niche [ ] Anti‐inflammatory macrophages are induced by interleukin‐4 (IL‐4), interleukin‐10 (IL‐10), interleukin‐13 (IL‐13), glucocorticoids or immune complexes, promote Th2 immunity and regulate wound healing and tissue remodeling. ] Inflammatory macrophages, which are activated by toll‐like receptors (TLR) ligands and interferon γ (IFN‐ γ), produce proinflammatory cytokines and induce a Th1 response to mediate host defense against infections and tumor cells. ] It is broadly believed that macrophages are activated by multiple signals and traditionally classified into two distinct subtypes: classically activated (M1) macrophages and alternatively activated (M2) macrophages. Macrophages play a dynamic role in the control of the tissue homeostasis, initiation of inflammation and modulation of inflammatory resolution. 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. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)‐high mobility group AT‐hook 2‐IGF2BP2‐peroxisome proliferator activated receptor‐ γ axis involves in M2 macrophages differentiation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6‐methyladenosine (m 6A)‐dependent manner. However, the IGF2BP2 −/− macrophages are refractory to interleukin‐4 (IL‐4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Here, it is observed that insulin‐like growth factor 2 messenger RNA (mRNA)‐binding protein 2 (IGF2BP2)‐deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment.
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