Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells

Abstract

Background & Aims Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Methods Propionibacterium acnes ( P. acnes )-primed, lipopolysaccharides (LPS)-induced FH was established in C57BL/6 mice and was treated with the Dot1L inhibitor EPZ-5676. Myeloid derived suppressor cells (MDSCs) were depleted by anti-Gr-1 antibody to evaluate their therapeutic roles in Dot1L treatment of FH. Moreover, peripheral blood of patients suffered with FH and healthy controls was collected to determine the expression profile of Dot1L-SOCS1-iNOS axis in their MDSCs. Results Here we identified that EPZ-5676, pharmacological inhibitor of Dot1L, attenuated the liver injury of mice subjected to FH. Dot1L inhibition led to decreased T helper 1 cell response and expansion of regulatory T cells (Tregs) during FH. Interestingly, Dot1L inhibition didn’t directly target T cells, but dramatically enhanced the immunosuppressive function of MDSCs. Mechanistically, Dot1L inhibition epigenetically suppressed SOCS1 expression, thus inducing inducible nitric oxide synthase (iNOS) expression in a STAT1-dependent manner. Moreover, in human samples, the levels of Dot1L and SOCS1 expression were upregulated in MDSCs, accompanied by decreased expression of iNOS in patients with FH, compared with healthy controls. Conclusions Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment.

Myeloid-derived suppressor cells promote the formation of abdominal aortic aneurysms through the IL-3-ICOSL-ICOS axis

“…The Gr-1-specific RB6–8C5 Ab is known to bind both Ly6G and Ly6C molecules, and two subsets of MDSCs sequentially lose their suppressive capacity after Gr-1 Ab treatment [59] . Based on the above characteristics, Gr-1-specific RB6–8C5 Ab is widely used to study the role of MDSCs in multiple types of tumors, inflammatory diseases, and autoimmune diseases [ 38 , 60 , 61 ]. In this study, to reveal the role of MDSCs in AAA, we depleted circulating MDSCs in AAA mice with an anti-Gr-1 antibody and found that depletion of MDSCs significantly reduced the incidence of AAA and reduced arterial wall rupture and elastin loss.…”

“…To evaluate the effect of MDSCs on AAA, anti-Gr-1 antibodies (clone: RB6–8C5, Biolegend, USA) were used to specifically deplete the circulating MDSCs in AAA mice; the method was performed as previously described [ 37 , 38 ]. Briefly, anti-Gr-1 antibodies were injected (200 μg, i.p.)…”

An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system

“…The authors observed a dependency on the presence of myeloid-derived suppressor cells (MDSC), as demonstrated through the depletion of these cells by injecting anti-GR-1 antibodies. Mechanistically, it was shown that the suppressive function of MDSCs was dramatically increased leading to the suppression of pathogenic CD4 + T cells, which contribute to disease progression ( 41 ). Interestingly, in this setting, inhibition of DOT1L with small molecule inhibitors did not have a direct effect on CD4 + T cells but only indirectly through MDSCs.…”

“…These studies collectively highlighted a role for DOT1L in B and T cell development, as well as lineage integrity and function. Other groups have also begun to characterise DOT1L in innate immune cell development and function including macrophages, bone marrow derived dendritic cells (BMDCs) and myeloid derived suppressor cells (MDSCs) (38)(39)(40)(41). This review will aim to consolidate our current knowledge about DOT1L in the context of the immune system (summarised in Table 1), whilst also discussing known and potential hypothetical mechanisms by which DOT1L may be regulating these biological pathways.…”