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.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that predominantly affects women in childbearing age and is associated with higher rates of mortality than the general population
A significant increase of proinflammatory monocytes was observed in lupus nephritis (LN) patients when compared with healthy controls (HC); no significant differences were observed when classical and anti-inflammatory monocytes were evaluated in both groups (Figure 1F)
We found that innate immune cells of patients with LN show lower expression of Heme oxygenase-1 (HO-1), have impaired functions at baseline, such as increased phagocytosis of opsonized beads and increased reactive oxygen species (ROS) production
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that predominantly affects women in childbearing age and is associated with higher rates of mortality than the general population. We have previously evaluated HO-1 expression in circulating monocytes of SLE patients, finding that this enzyme is decreased in affected individuals [3] and in an animal model for SLE [4]. Kidneys from CO-treated lupus mice have less number of activated B220+CD4−CD8− T cells than control animals and present delayed renal failure [4]. It is well-known that, in LN, renal damage is initiated by glomerular deposition of immune complexes (IC) and subsequent complement activation, it has been acknowledged that innate immune cells play an active role in the propagation of tissue damage. Elegant experiments using a humanized lupus mouse model show that SLE human serum is capable of inducing LN in a process mediated by infiltrating neutrophils recruited by an FcγRIIA-dependent mechanism [11]
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