Heme-Oxygenase-1 Is Decreased in Circulating Monocytes and Is Associated With Impaired Phagocytosis and ROS Production in Lupus Nephritis

Abstract

Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE). Based on studies showing the potential role of heme oxygenase-1 (HO-1), an enzyme that catalyzes the degradation of heme and has anti-inflammatory properties in SLE development, we decided to explore HO-1 in LN. Accordingly, we evaluated HO-1 levels and function in circulating and infiltrating monocytes and neutrophils of LN patients. HO-1 levels were assessed in peripheral monocytes of LN patients and controls by flow cytometry and immunofluorescence microscopy. Phagocytosis and the production of reactive oxygen species (ROS) were evaluated to determine the effect of HO-1 in monocyte function. In addition, renal biopsies with proliferative LN were used to identify HO-1 in infiltrating cells and renal tissue by immunofluorescence and immunohistochemistry. Biopsies of healthy controls (HC) and patients who underwent nephrectomy were included as controls. Circulating pro-inflammatory monocytes and activated neutrophils were increased in LN patients. HO-1 levels were decreased in all subsets of monocytes and in activated neutrophils. LN monocytes showed increased phagocytosis and higher production of ROS than those of HC. When HO-1 was induced, phagocytosis and ROS levels became similar to those of HC. HO-1 was mostly expressed in renal tubular epithelial cells (RTEC). Renal tissue of LN patients showed lower levels of HO-1 than HC, whereas infiltrating immune cells of LN showed lower levels of HO-1 than biopsies of patients who had renal surgery. HO-1 is decreased in circulating monocytes and activated neutrophils of LN patients. HO-1 levels modulate the phagocytosis of LN monocytes and ROS production. HO-1 expression in RTEC might be an attempt of self-protection from inflammation.

Exploring the Differences in Molecular Mechanisms and Key Biomarkers Between Membranous Nephropathy and Lupus Nephritis Using Integrated Bioinformatics Analysis

“…In addition, there are many differences between MN and LN. Although both are autoimmune diseases, renal pathology of LN shows glomerular intrinsic cell proliferation and circulating inflammatory cell infiltration, while MN rarely shows these pathological changes ( Cuitino et al, 2019 ; Motavalli et al, 2019 ; Sung and Fu, 2020 ). The pathogenic antibody of MN is IgG, and IgG4 is the main type ( Liu et al, 2020 ).…”

Hsa_circ_0010957 knockdown attenuates lipopolysaccharide-induced HK2 cell injury by regulating the miR-1224-5p/IRAK1 axis

“…By detecting release of these cytokines using ELISA, we found that hsa_circ_0010957 silence weakened LPS-induced inflammatory injury in HK2 cells. In addition, oxidative injury is another factor for lupus nephritis [ 28 , 29 ]. Through detecting the levels of oxidative stress-associated ROS and LDH and anti-oxidative SOD activity, we found that hsa_circ_0010957 silence attenuated LPS-induced oxidative injury.…”

The Role of Heme Oxygenase-1 as an Immunomodulator in Kidney Disease

“…Further studies of LN patients by Cuitino et al confirm low HO-1 expression in pro-inflammatory monocytes and activated neutrophils with unbalanced function, such as increased phagocytosis and ROS production [ 57 ]. Interestingly, cobalt protoporphyrin (Co-PP) seems to induce HO-1 expression with a subsequent modification of LN monocyte phagocytic activity to a level similar to that of healthy controls.…”

“…Interestingly, cobalt protoporphyrin (Co-PP) seems to induce HO-1 expression with a subsequent modification of LN monocyte phagocytic activity to a level similar to that of healthy controls. Thus, we can speculate that the impaired LN monocyte and neutrophil activity could be in part explained by reduced levels of HO-1 [ 57 ]. However, further studies are needed to confirm this hypothesis.…”