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

Abstract

Immune-driven dry eye disease primarily affects women; the cause for this sex-specific prevalence is unknown. PMN have distinct phenotypes that drive inflammation but also regulate lymphocytes and are the rate-limiting cell for generating anti-inflammatory lipoxin A4 (LXA4). Estrogen regulates the LXA4 circuit to induce delayed female-specific wound healing in the cornea. However, the role of PMN in dry eye disease remains unexplored. We discovered a LXA4-producing tissue-PMN population in the corneal limbus, lacrimal glands and cervical lymph nodes of healthy male and female mice. These tissue-PMN, unlike inflammatory-PMN, expressed a highly amplified LXA4 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 LXA4 formation that remained depressed during dry eye disease. Depressed lymph node PMN and LXA4 in females correlated with an increase in T effector cells (TH1 and TH17), a decrease in regulatory T cells (Treg) and increased dry eye pathogenesis. Antibody depletion of tissue-PMN abrogated LXA4 formation in lymph nodes, caused a marked increase in TH1 and TH17 and decrease in Treg cells. To establish an immune regulatory role for PMN-derived LXA4 in dry eye females were treated with LXA4. LXA4 treatment markedly inhibited TH1 and TH17 and amplified Treg cells in draining lymph nodes, while reducing dry eye pathogenesis. These results identify female-specific regulation of LXA4-producing tissue-PMN as a potential key factor in aberrant T effector cell activation and initiation of immune-driven dry eye disease.

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

“…Control mice were maintained in a non-stressed (NS) environment containing 50–75% relative humidity without exposure to forced air. Since dry eye is more prevalent in women and male mice do not respond well to desiccation, only female mice were used (Gao et al, 2015; Schaumberg et al, 2003, 2009). …”

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

“…The results from this study from Resolvyx Pharmaceuticals, for which CNS was the original scientific founder, were the first demonstration of clinical efficacy with pro-resolving agents in humans (Business Wire, 2009; de Paiva et al, 2012). The Phase II trial controlling inflammation in the eye with topical drops (Business Wire, 2009) was based on the physiologic roles (Gronert, 2010; Li et al, 2010; Erdinest et al, 2014) of SPM such as resolvins and lipoxins in the eye (Li et al, 2013; Hodges et al, 2016; Dartt et al, 2011; Cortina and Bazan, 2011) and apparent gender differences, where females display delayed wound healing of cornea tissue and reduced 15-LOX-derived SPM such as lipoxin A 4 (Gao et al, 2015; Wang et al, 2012). Since 15- R/S -methyl lipoxin A 4 , an analog of the aspirin-triggered form of lipoxin A 4 , one of the first stop signals and pro-resolving mediators, is effective in infantile eczema in a double-blind, placebo-controlled study randomized at two different centers (Wu et al, 2013), and LXA 4 , resolvin D1, RvD2 and maresin 1 act on T-cell responses (Chiurchiu et al, 2016; Gao et al, 2015), it is likely that SPM have physiologic roles in human skin and barrier functions that remain to be studied, and their functions extend from the resolution phase into the adaptive immune response (Ramon et al, 2012).…”

Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders

“…Endogenous lipoxin A4 promotes corneal ephitelial wound healing [76], inhibits pathological angiogenesis and proinflammatory cytokine expression [77,78], and controls effector T-cell activation [79]. Neuroprotectin D1 is implicated in epithelial cell survival [80], recovery from oxidative stress and wound healing [81]; it has also been shown to promote corneal nerve regeneration and return of corneal sensitivity [81,82].…”