Histone demethylases in the regulation of immunity and inflammation

Abstract

Pathogens or danger signals trigger the immune response. Moderate immune response activation removes pathogens and avoids excessive inflammation and tissue damage. Histone demethylases (KDMs) regulate gene expression and play essential roles in numerous physiological processes by removing methyl groups from lysine residues on target proteins. Abnormal expression of KDMs is closely associated with the pathogenesis of various inflammatory diseases such as liver fibrosis, lung injury, and autoimmune diseases. Despite becoming exciting targets for diagnosing and treating these diseases, the role of these enzymes in the regulation of immune and inflammatory response is still unclear. Here, we review the underlying mechanisms through which KDMs regulate immune-related pathways and inflammatory responses. In addition, we also discuss the future applications of KDMs inhibitors in immune and inflammatory diseases.

Fig. 1. Schematic diagram of two families of human KDMs.

The key domains of each KDMs are represented in colored regions, and the number of amino acids is written in each functional domain. SWIRM Swi3p, Rsc8p, and Moira domain; JmjC Jumonji C domain, JmjN Jumonji N domain, ARID AT-rich interacting domain, PHD plant homeodomain domain, F-box F-box domain, LRR Leu-rich repeat domain, TPR tetratricopeptide domain, Tudor Tudor domain, CW CW-type zinc-finger domain, C6 C6 zinc-finger domain, CXXC CXXC zinc-finger domain, C5HC2 C5HC2 zinc-finger domain.

Fig. 2. Five major demethylation sites of KDMs in histones H3 and H4 (red).

The number above the site refers to the rank number of each lysine residue in the histone.

Fig. 3. Regulatory mechanisms of KDMs in lymphocytes, NK cells, and macrophages differentiation.

The KDM6 subfamily is important for the development of T lymphocytes. KDM6A and KDM6B promote the expression of S1pr1 and Klf2, crucial for the maturation of T cells, by targeting promoter H3K27me3. Subsequently, KDM6B modifies the expression of Th17-related genes including Il22, Il17f, Il17, Rorγt, and Th1-related genes including T-bet and Smad3, promoting the differentiation into Th17 and Th1 cells, respectively. During the differentiation of B cells, KDM1A takes part in repressing PU.1, IRF4 and Blimp-1 through decreasing H3K4me3, which is crucial for the formation of plasmablasts. KDM5A recruited by p50 is responsible for the downregulation of Socs1 through erasing H3K4me3 in NK cells, inducing IFN production. In macrophages, KDM3C modulates H3K9me of the miR-302a promoter and inhibits M1 macrophage differentiation via the miR-302a/METTL3 axis. Finally, the KDM6B/IFR4 axis promotes the differentiation of M2 macrophages.

Fig. 4. Regulation of innate immune pathways by KDMs.

KDMs regulate TLR, cGAS-STING, and IFN signaling pathways to modulate inflammation and antiviral responses. (1) TLRs signaling pathway. KDM4D promotes TLR4 transcription by demethylating H3K9, thereby activating the TLR4/TIRAP/MyD88/NF-κB signaling pathway, which in turn promotes the expression of hepatic fibrosis factors COL1A1, ACTA2, VIM, and inflammatory cytokines TNF-α and IL-1β. Increasing the expression of KDM5A can inhibit Pten, activate PI3K/AKT/S6K1/PD-L1 and TLR7/8 signaling pathways, and promote the expression of cytokines and chemokines. (2) After viral infection of cells, KDM5B/5 C can inhibit STING expression by demethylation of H3K4me3, while KDM5 inhibitors increase IFN levels and improve antiviral immune response by enhancing the cGAS-STING-TBK1-IRF3 pathway. (3) Inhibition of KDM1A in cells induces the level of SESN2, which activates the autophagy-related PI3K/Akt/mTOR pathway, ultimately inhibiting the activation of the NLRP3 inflammasome. At the same time, it increases KDM6B and promotes ASC/NLRP3/Caspase, hence promoting the inflammatory response.