m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs

Abstract

Microglia are brain resident cells that function as brain phagocytic macrophages. The inflammatory responses of microglia induced by pathologic insults are key regulators in the progression of various neurological disorders. Currently, little is known about how these responses are regulated intrinsically. Here, it is observed that LPS-activated microglia exhibit distinct N6-methyladenosine (m6A) methylation patterns that are positively correlated with the expression patterns of corresponding mRNAs. High-throughput analyses and molecular studies both identified Igf2bp1 as the most significantly regulated m6A modifiers in activated microglia. Perturbation of function approaches further indicated Igf2bp1 as a key mediator for LPS-induced m6A modification and microglial activation presumably via enhancing the m6A methylation and stability of Gbp11 and Cp mRNAs. Thus, our study provides a possible mechanism for the m6A methylation-mediated microglia regulation and identifies Igf2bp1 as a potential target for modulating the inflammatory responses of microglia.

Internal m7G methylation: A novel epitranscriptomic contributor in brain development and diseases

“…More important, these types of cells are with high heterogeneity. We, together with other independent groups, have demonstrated the distinct mRNA m6A signatures of brain tissues 126 and specific cell types including microglia 46 , 127 under pathological conditions (e.g., hypoxia, neuroinflammation). Similarly, mRNA m7G profiles are highly likely to be altered during neurodevelopment and the progressions of neurological disorders, which can be addressed by m7G MeRIP-seq and other high-throughput analyses.…”

“… 44 Our recent RNA-seq analyses also suggested significant up-regulation of Trmt112 expression in differentiating neural stem cells, 128 and reduction of expression levels of Wbscr22 transcripts in activated microglia. 46 These results provide confidence to clarify the contribution of the deregulation of WBSCR22/TRMT112 expression and rRNA m7G modification disorder on brain development and diseases in future studies.…”

“… 29 , 32 Interestingly, multiple studies have demonstrated altered expression of WBSCR22 and TRMT112 in various pathological conditions, including various cancers 44 , 45 and inflammation. 46 , 47 These findings imply potential contribution of WBSCR22/TRMT112 complex-mediated rRNA m7G modification on human diseases, which needs to be confirmed in future work.…”

Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway

“…Meanwhile, genetic and pharmacological inhibition of METTL3, a typical m6A writer, attenuated renal injury and inflammation [68,69]. IGF2BP1 is one of the common m6A readers but has not been reported in septic AKI; however, studies confirmed that its level could be elevated when induced by LPS and regulate the inflammatory responses [24,70]. In addition, IGF2BP1 was previously reported to promote proliferation in vitro and growth in vivo in an m6A-dependent manner [71,72].…”

m6A methylation: Critical roles in aging and neurological diseases

“…Studies suggest that METTL3 promotes lipopolysaccharide (LPS)-induced microglial inflammation by activating the TNF receptor associated factor 6 (TRAF6)-NF-κB pathway ( Wen et al, 2022 ) and improves neuronal apoptosis and microglial activation by inactivating MyD88/NF-κB pathway ( Chen Y. et al, 2022 ). In addition, m6A reader Igf2bp1 is reported to regulate the inflammatory processes of microglia via enhancing the m6A methylation and stabilizing Gbp11 and Cp mRNAs ( Ding et al, 2022 ). It is reported that microRNA-421–3p could prevent inflammatory response in cerebral ischemia/reperfusion injury through targeting m6A reader YTHDF1 to inhibit p65 mRNA translation, which may provide a target for ischemia treatment ( Zheng et al, 2020 ).…”