Female-Specific Downregulation of Tissue Polymorphonuclear Neutrophils Drives Impaired Regulatory T Cell and Amplified Effector T Cell Responses in Autoimmune Dry Eye Disease

Immune-driven dry eye disease primarily affects women; the cause for this sex-specific prevalence is unknown. Polymorphonuclear neutrophils (PMN) have distinct phenotypes that drive inflammation but also regulate lymphocytes and are the rate-limiting cell for generating anti-inflammatory lipoxin A(4) (LXA(4)). Estrogen regulates the LXA(4) circuit to induce delayed female-specific wound healing in the cornea. However, the role of PMNs in dry eye disease remains unexplored. We discovered an LXA(4)-producing tissue PMN population in the corneal limbus, lacrimal glands, and cervical lymph nodes of healthy male and female mice. These tissue PMNs, unlike inflammatory PMNs, expressed a highly amplified LXA(4) circuit and were sex-specifically regulated during immune-driven dry eye disease. Desiccating stress in females, unlike in males, triggered a remarkable decrease in lymph node PMN and LXA(4) formation that remained depressed during dry eye disease. Depressed lymph node PMN and LXA(4) in females correlated with an increase in effector T cells (Th1 and Th17), a decrease in regulatory T cells (Treg), and increased dry eye pathogenesis. Ab depletion of tissue PMN abrogated LXA(4) formation in lymph nodes, as well as caused a marked increase in Th1 and Th17 cells and a decrease in Tregs. To establish an immune-regulatory role for PMN-derived LXA(4) in dry eye, females were treated with LXA(4). LXA(4) treatment markedly inhibited Th1 and Th17 and amplified Treg in draining lymph nodes, while reducing dry eye pathogenesis. These results identify female-specific regulation of LXA(4)-producing tissue PMN as a potential key factor in aberrant effector T cell activation and initiation of immune-driven dry eye disease.