Leishmania donovani Subverts Host Immune Response by Epigenetic Reprogramming of Macrophage M(Lipopolysaccharides + IFN-γ)/M(IL-10) Polarization

Abstract

Reciprocal changes in histone lysine methylation/demethylation of M(LPS + IFN-g)/M(IL-10) genes is one of the factors that direct macrophage polarization and contribute to host defense/susceptibility toward infection. Although, histone lysine methyltransferases and lysine demethylases orchestrate these events, their role remains elusive in visceral leishmaniasis, a disease associated with macrophage M(IL-10) polarization. In this study, we observed that L. donovani induced the expression of histone lysine methyltransferases Ash1l, Smyd2, and Ezh2 and histone lysine demethylases Kdm5b and Kdm6b in J774 macrophages and BALB/c mice. Chromatin immunoprecipitation analysis revealed that L. donovani facilitated H3K36 dimethylation at TNF-a promoter by Smyd2 and H3K27 trimethylation at inducible NO synthase promoter by Ezh2 to suppress their expression in macrophages. Furthermore, infection-induced Kdm5b and Kdm6b modulated H3K4 and H3K27 trimethylation at IL-12, TNF-a, and arginase-1 promoters, respectively, whereas H3K4 trimethylation by Ash1l at IL-10 promoter induced its expression. Analysis of transductional events revealed that HIF-1a upregulated Kdm5b and Kdm6b expression, whereas Ash1l and Ezh2 expression were induced by transcription factor MeCP2. Additionally, Smyd2 was induced by c-Myc in infected macrophages. Knockdown of Ash1l, Ezh2, Kdm5b, and Kdm6b by specific small interfering RNA and Vivo-Morpholino, as well as inhibition of Smyd2 by its specific inhibitor, AZ505, led to increased protective proinflammatory response and inhibited amastigote multiplication in infected J774 macrophages and BALB/c mice, respectively. Collectively, our findings demonstrate that L. donovani exploits specific histone lysine methyltransferases/demethylases to redirect epigenetic programming of M(LPS + IFN-g)/M(IL-10) genes for its successful establishment within the host.

Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis

“…Previous studies have demonstrated that in addition to TGF-β/Smad3, other signaling pathways such as STAT3, NF-kB, ERK1/2, and AKT, are activated and involved in cellular events, including survival, proliferation, and inflammation during the course of renal fibrosis. [8][9][10][11][12][34][35][36][37][38] Our current studies showed that SMYD2 inhibition blocked phosphorylation of all these signaling molecules in vivo and in vitro, supporting the importance of these pathways in transducing SMYD2 activation to renal fibrogenesis. The mechanism by which SMYD2 controls phosphorylation and activation of intracellular signaling molecules remains incompletely understood but is being explored.…”

Super enhancer-mediated transcription of miR146a-5p drives M2 polarization during Leishmania donovani infection

“…Understanding of miRNA regulation during parasite infection by high order chromatin elements like SE will add a new dimension to Leishmania infection biology. Parmar et al recently established that L. donovani infection mediates macrophage polarization by broad range histone make over in polarized macrophages [34]. Our observations additionally highlight novel roles of super enhancers and epigenetic regulator protein BRD4 in sustained miR146a-5p expression during L. donovani infection which can be a promising juncture for transcriptional perturbation based therapeutics against VL.…”

The SMYD family proteins in immunology: An update of their obvious and non-obvious relations with the immune system

“…Pharmacological inhibition of SMYD2 using AZ505 enhanced the protective inflammatory response in infected macrophage cell lines and decreased parasite multiplication in infected mice. Thus, SMYD2, along with other methyltransferases, aids Leishmania donovani in the process of infecting the host ( Parmar et al., 2020 ). Moreover, using human CD4+ cells lines and T cells from human immunodeficiency virus type 1 (HIV-1)-infected donors, Boehm et al.…”

“…Nonetheless, SMYD2 enzymatic activity is not restricted to H3K36, and this enzyme can also act on histone 4 lysine 20 (H4K20), among other targets ( Boehm et al., 2017 ; Yi et al., 2019 ). Through its methylatse activity, SMYD2 helps Leishmania donovani to infect the host organism ( Parmar et al., 2020 ) and activates HIV-1 latency ( Boehm et al., 2017 ). Furthermore, the majority of the data indicates that SMYD2 acts as an oncogene in blood malignancies, although there is some controversy.…”