The role of RNA modifications in disease-associated macrophages

Abstract

In recent years, the field of epitranscriptomics has witnessed significant breakthroughs with the identification of more than 150 different chemical modifications in different RNA species. It has become increasingly clear that these chemical modifications play an important role in the regulation of fundamental processes linked to cell fate and development. Further interest was sparked by the ability of the epitranscriptome to regulate pathogenesis. However, despite the involvement of macrophages in a multitude of diseases, a clear knowledge gap exists in the understanding of how RNA modifications regulate the phenotype of these cells. Here, we provide a comprehensive overview of the known roles of macrophage RNA modifications in the context of different diseases.

Keywords: MT: RNA and epigenetic editing Special Issue; RNA modification; epitranscriptomics; m6A; macrophages.

Graphical abstract

Figure 1

Schematic representation of the m6A RNA modification complex The m6A methylation is catalyzed by the writer complex, including METTL3, METTL14, METTL16, WTAP, vir-like m6A methyltransferase-associated (VIRMA), RBM15/15B, zinc-finger CCCH-type-containing 13 (ZC3H13), zinc finger CCHC-type containing 4 (ZCCHC4), oncogene-like protein 1 (CBLL1), METTL5, and tRNA methyltransferase activator subunit 11-2 (TRMT112). The m6A modification is erased by demethylases, including FTO and ALKBH5. The m6A-modified RNA reader proteins include YTHDFs, YTHDCs, IGF2BPs, heterogeneous nuclear ribonucleoproteins (HNRNPs), and FMRP. The m6A modification modulates the following processes: microRNA biogenesis, RNA export, alternative splicing, RNA translation, RNA decay, and RNA stability.

Figure 2

m6A modifications and the mechanisms of their involvement in regulating disease-associated macrophages (A) Mettl3, Mettl14, and Fto regulate the phenotype of brain macrophages through distinct response mechanisms. (B) Mettl3 regulates liver macrophages. (C) Igf2bp2, Ythdf2, and Mettl3 regulate the phenotype of lung macrophages. (D) Igf2bp2 regulates the phenotype of gastrointestinal macrophages. (E) Alkbh5 regulates the phenotype of cardiac macrophages.

Figure 3

The role of macrophage m6A in the context of infection The absence of the writer complex (Mettl3/Mettl14) in macrophages increased bacterial burden (Salmonella typhimurium) as well as the symptoms linked to sepsis. The absence of the erasers (Fto and Alkbh5) in macrophages led to decreased symptoms of sepsis following the administration of a lethal LPS dose and upon viral infection (VSV). The absence of Ythdf1, an m6A reader, in macrophages decreased the expression of pro-inflammatory cytokines.

Figure 4

The role of macrophage m6A in the context of cancer The absence of the writer complex (Mettl3/Mettl14) in macrophages either has an anti-tumoral or a pro-tumoral role. The same holds true for the absence of Ythdf2, an m6A reader.