Contact-Dependent Depletion of Hydrogen Peroxide by Catalase Is a Novel Mechanism of Myeloid-Derived Suppressor Cell Induction Operating in Human Hepatic Stellate Cells

Abstract

Myeloid-derived suppressor cells (MDSC) represent a unique cell population with distinct immunosuppressive properties that have been demonstrated to shape the outcome of malignant diseases. Recently, human hepatic stellate cells (HSC) have been reported to induce monocytic-MDSC from mature CD14+ monocytes in a contact-dependent manner. We now report a novel and unexpected mechanism by which CD14+HLADRlow/− suppressive cells are induced by catalase-mediated depletion of hydrogen peroxide (H2O2). Incubation of CD14+ monocytes with catalase led to a significant induction of functional MDSC compared with media alone, and H2O2 levels inversely correlated with MDSC frequency (r = −0.6555, p < 0.05). Catalase was detected in primary HSC and a stromal cell line, and addition of the competitive catalase inhibitor hydroxylamine resulted in a dose-dependent impairment of MDSC induction and concomitant increase of H2O2 levels. The NADPH-oxidase subunit gp91 was significantly increased in catalase-induced MDSC as determined by quantitative PCR outlining the importance of oxidative burst for the induction of MDSC. These findings represent a so far unrecognized link between immunosuppression by MDSC and metabolism. Moreover, this mechanism potentially explains how stromal cells can induce a favorable immunological microenvironment in the context of tissue oxidative stress such as occurs during cancer therapy.

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

“…146 In mice, activated HSCs can induce expansion and accumulation of MDSCs derived from myeloid progenitor cells, which is mediated by IL-6, 149 CD44, complement component 3, 150 COX-2, and catalase-mediated depletion of hydrogen peroxide. [151][152][153][154] Also, HSC-derived SDF-1 plays a crucial role in MDSC migration in the mouse HCC model. 155 Based on these findings, preventing MDSC induction and infiltration could be an effective strategy for HCC therapy.…”

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

“…In another study, it was indicated that monocytic MDSCs are induced by catalase-mediated exhaustion of hydrogen peroxide from mature CD14+ monocytes, and the frequency of MDSC inversely correlated with hydrogen peroxide level. The oxidative stress in many liver diseases with decreased activity of catalase and increased hydrogen peroxide might inhibit the expansion and activation of hepatic MDSCs that are expected to resolve overimmune response [138]. Therefore, oxidative stress might serve as a mediator of impeding immune suppression response to promote inflammation.…”

Tumor regulation of the tissue environment in the liver

“…This HSC-monocyte interaction results in early tumor recurrence and poor survival of liver cancer patients (Ji, et al, 2015). Moreover, they can induce the contact-dependent accumulation of MDSC, either through CD44 on HSC or through hydrogen peroxide depletion by catalase (Hochst, et al, 2013; Resheq, et al, 2015). HSC can also directly trigger T cell dysfunction through pathways analogous to other immunosuppressive cells.…”