Background/Purpose: Lupus glomerulonephritis (GN) is a leading cause of long-term disability in SLE. Although lupus is more common in females, GN occurs earlier and in a more accelerated manner in males. We propose that the severity of renal damage is defined by differences in cell death program during GN. Necrosis, a pro-inflammatory form of cell death can be regulated by two mediators: 1) Poly (ADP-Ribose) Polymerase-1 (PARP-1) and 2) Receptor Interacting Protein kinase 1/3 (RIP1/3). We demonstrated previously that the protection conferred by the absence or inhibition of PARP-1 from immune-mediated nephritis shows a sex-bias, with only male mice being protected. Several studies have shown that the response of males and females to stress differs. We therefore hypothesized that these differences might be due to cell death programs in the two sexes.

Methods:

We used an established model of immune complex mediated nephritis to investigate cell death in vivo and an in vitro system where bone marrow cells were allowed to differentiate in vitro into macrophages in presence or absence of estrogens. The cells were stimulated by hydrogen peroxide or toll-like receptor ligand (TLR), lipopolysaccharide (LPS). Cell death was measured by flow cytometry and morphology; cytokine were measured by quantitative PCR.

Results: We demonstrate that during nephritis, females show increased apoptotic cell death in the kidney compared to males. We also show that estrogen treatment in males induced similar levels of apoptosis as in females and importantly inhibited necrosis.  Although PARP-1 was activated in both males and females, PARP-1 inhibition decreased necrosis only in males. Interestingly inhibition of RIP1 with Necrostatin-1 did not show sex bias. To understand whether male and female cells show a differential cytokine expression pattern that may further contribute to the differences in cell death, we determined cytokine gene expression by bone marrow derived macrophages from male and female cells in response to TLR ligation in presence or absence of estrogens. We found that the expression of pro-inflammatory cytokines TNF alpha and MCP-1 were higher in male cells in absence of estrogens compared to females, suggesting that these cytokines may contribute to increased necrosis observed in males. We also observed that estrogens increased IL10 production in male cells upon TLR ligation. Interestingly IL10 has been previously shown to inhibit necrosis. Finally we found that estrogens reduced the levels of pro-inflammatory cytokines TNF alpha and MCP1.

Conclusion:

Taken together our data suggest that males and females differ in their susceptibility to pro-inflammatory cell death, i.e. propensity toward necrosis in males and apoptosis in females. The contributing factors to this dichotomy are the effective activation of necrotic cell death, hormones and pro-inflammatory cytokines. Our results might help understanding the increased severity of lupus nephritis in males and develop novel therapeutic strategies based on sex.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/different-cell-death-programs-contribute-to-severity-of-lupus-glomerulonephritis-in-males-and-females/