Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Abstract

Keywords: mitochondria, succinate dehydrogenase, bone marrow transplantation, graft-versus-host 22 disease, intestinal epithelium 23 24 25Summary 26Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic 27 diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune 28 checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding 29 the aberrant biology of T cells in these diseases, little is known about how the fundamental biological 30 processes of the target IECs influence the disease severity. Here, through analyses of metabolic 31 pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change 32 in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated 33 mediated gastrointestinal graft-versus-host disease (GI-GVHD) often have similar symptoms and cause 50 significant morbidity and mortality 1 5 6 . Although the pathophysiology of each of these diseases is a 51 complex interplay of the environmental and genetic factors, T cell mediated damage of IECs plays a 52 vital role in the cause and severity of all of these conditions. Immunosuppression with corticosteroids, 53 and anti-cytokine therapies have shown good results with adverse effects, but are still incomplete 5 7 8 . 54The biology and treatments of these diseases are often understood and targeted from the immune cell 55 3 and inflammation perspective, but the pathogenesis and severity from host IEC target cell perspective 56 remain undefined. 57 58 Emerging data in recent years have brought into focus the central role of immune cell metabolism in the 59 regulation of intestinal inflammatory diseases. APCs, including macrophages and dendritic cells, and T 60 cells show changes in metabolic programming, including morphological alterations in mitochondria, 61transitioning from glycolysis dependence (pro-inflammatory macrophages and effector T cells) to 62 oxidative phosphorylation (OXPHOS) dependence (anti-inflammatory macrophages and memory T 63 cells) 9 10 11 and regulate intestinal T cell mediated diseases such as GI GVHD and IBD. However, 64whether the metabolism of the targets of these pathogenic T cells in these diseases, the IECs, are 65 perturbed or reprogrammed, and if so, whether this has an impact on the disease severity remains 66 unknown. The mammalian GI tract is a relatively hypoxic region and thus, IECs are uniquely adapted to 67 this hypoxic environment 12 13 . In this study, we aimed to determine the metabolic changes in IECs when 68 they are targeted by pathogenic T effector cells. We found that in the context of pathogenic T cell 69 mediated damage, the IECs demonstrated a reduction in OXPHOS and accumulated succinate as a result 70 of decrease in SDHA, a component of mitochondrial complex II. The reduction of SDHA in IECs 71 aggravated disease severity in multiple T cell mediated models such as the alloimmune mediated GI 72 GVHD, ...

A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation

“…C57BL/6N-Sdha tm2a(KOMP)Wtsi mice were obtained from the Knock Out Mouse Project (KOMP) repository, University of California, Davis (Davis, CA, USA) and bred to ACTFLPe mice to excise the FRT-flanked region. The resulting Sdha fl/fl mice were bred to Vil1-Cre mice to create Vil1-Cre Sdha fl/fl (Sdha ∆/IEC ) mice (32). Then,12-15 week-old mice were used in our experiments.…”

A redox cycle with complex II promotes sulfide quinone oxidoreductase dependent H2S oxidation

“…To assess the physiological relevance of our observation that H 2 S clearance is supported by complex II working in reverse, we measured the impact of attenuating complex II on organismal H 2 S metabolism. For this, mice harboring loxP-flanked Sdha were crossed to mice expressing Cre recombinase under control of the villin promoter to specifically target intestinal epithelial cells, to generate Vil1-Cre Sdha fl/fl (Sdha ΔIEC ) mice as described previously (31). The rationale for targeting intestinal epithelial cells is that they are routinely exposed to high concentrations of H 2 S (23, 24) and actively oxidize sulfide (13).…”

“…No reuse allowed without permission. expressing Cre recombinase under control of the villin promoter to specifically target intestinal epithelial cells, to generate Vil1-Cre Sdha fl/fl (Sdha IEC ) mice as described previously (31). The rationale for targeting intestinal epithelial cells is that they are routinely exposed to high concentrations of H 2 S (23, 24) and actively oxidize sulfide (13).…”

Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease

“…In aGVHD and cGVHD intestinal damage and microbial dysbiosis are central to pathogenesis ( 1 , 2 ). Indeed, intestinal epithelial cell (IEC) damage has been shown to contribute to alloimmune and autoimmune diseases such as inflammatory bowel disease (IBD) and GVHD ( 62 , 63 ). IECs form mucosal and chemical barriers including antimicrobial peptides to protect the host from invading pathogens ( 64 ).…”

“…IECs form mucosal and chemical barriers including antimicrobial peptides to protect the host from invading pathogens ( 64 ). A recent study investigated the metabolic changes of IECs in aGVHD mice ( 62 ). Oxygen consumption rates (OCR), an indicator of OXPHOS, in allogeneic IECs (allo-IECs) were significantly lower from syngeneic IECs (syn-IECs) controls.…”