Background/Purpose: Systemic Lupus Erythematosis (SLE) is a multisystem autoimmune disease that develops far more frequently in females than in males (9:1 ratio). The (NZBxNZW)F1 lupus-prone mouse model shares a female predominance of disease. Our recently published studies have shown decreased numbers of Gr1⁺CD11b⁺ cells in the spleens of female (NZBxNZW)F1 lupus-prone mice compared to males and that the level of these cells is modulated by testosterone. These cells have been found by our lab and others to suppress both T and B cell function in vitro. Depletion of this cell subset in male (NZBxNZW)F1 mice resulted in increased anti-nuclear antibody production. We suggest that the difference in cell numbers has a role to play in the gender differences in lupus-like disease development. We aimed to investigate the mechanism driving the difference in numbers of Gr1⁺CD11b⁺ cells in male and female mice. We hypothesized that the comparatively decreased levels of Gr1⁺CD11b⁺ cells in the female (NZBxNZW)F1 mice is due to either their decreased proliferative capacity or to their decreased survival.

Methods: Levels of proliferation and cell death of Gr1⁺CD11b⁺ cells from male and female (NZBxNZW)F1 mice were determined ex vivousing anti-Ki67 and Annexin V antibodies, respectively. The effect of hormonal manipulation on proliferation and cell death was assessed through pre-pubertal castration of male mice followed by DHT or placebo supplementation for 5 weeks. Total spleen and bone marrow cells from male and female mice were cultured in various conditions to determine the effect of cytokines and components of the male and female microenvironments on proliferation and cell death.

Results: Proliferation levels were not different in Gr1⁺CD11b⁺ cells from male and female mice, and these levels were unaffected by castration and DHT supplementation. Apoptosis levels were significantly higher in Gr1⁺CD11b⁺ splenocytes from female mice compared to male mice. There was no defect in clearance of apoptotic material in female (NZBxNZW)F1 mice compared to males. The level of cell death was elevated by castration of male mice, but not statistically significantly. Components of the male and female microenvironments were examined for their ability to alter levels of cell death in vitro, and we found that male bone marrow supernatants can significantly increase the survival of Gr1⁺CD11b⁺ cells when compared to female supernatants. We found higher levels of IL-1β in the male bone marrow supernatants and the level of IL-1β was modulated by castration and hormonal reconstitution. Culture of bone marrow cells from male and female (NZBxNZW)F1 mice with IL-1β significantly increased the survival of Gr1⁺CD11b⁺cells.

Conclusion: Increased apoptosis of female Gr1⁺CD11b⁺ cells may represent one of several mechanisms by which these cells are decreased in female mice compared to males, allowing autoimmunity to develop. The death of  Gr1⁺CD11b⁺ cells was significantly decreased by exposure to male bone marrow supernatants in vitro, suggesting that the male microenvironment may support the survival of these cells. Additionally, our data implies that differences in IL-1β may be the factor in the male system that supports the survival of Gr1⁺CD11b⁺ cells.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-survival-of-gr1cd11b-cells-is-differentially-regulated-in-male-and-female-lupus-prone-mice/