Polymophonuclear leukocytes (PMNL) have largely been ignored in the etiology or pathogenesis of ocular immune responses. PMNL presumed ocular role is host defense and they are considered secondary recruited pro-inflammatory cells that cause downstream collateral tissue damage. However, the dogma of a single primitive inflammatory PMNL cell type is rapidly evolving in other organ systems and distinct populations of PMNL are now recognized that regulate lymphocyte function. An immune-driven ocular disease, whose pathogenesis is initiated by aberrant activation of effector T cells, is aqueous tear deficient Dry Eye Disease, which is one of the most frequent ocular morbidities and has a striking female prevalence. The role of PMNL in Dry Eye Disease has not been investigated. A primary function of PMNL is formation and release of eicosanoids and receptors for these lipid mediators are expressed in lymphocytes. However, eicosanoid regulation of lymphocytes is a relatively unexplored area of immune regulation. In addition to driving host defense, PMNL are also the rate limiting cell type for generating the anti-inflammatory eicosanoid lipoxin A4 (LXA4). We recently provided the first evidence for marked sex-specific differences in corneal injury responses in both humans and mice and identified estrogen downregulation of an epithelial LXA4 circuit as a mechanism for delayed wound healing in females. In pilot studies, we discovered a novel LXA4-producing tissue-PMNL population in corneal limbus, lacrimal glands and cervical lymph nodes of healthy males and females. This tissue-PMNL, unlike inflammatory-PMNL, express a highly amplified LXA4 circuit and are dynamically and sex- specifically regulated during immune-driven Dry Eye Disease. The most striking sex-specific differences was that desiccating stress in females, unlike in males, triggered a remarkable decrease in lymph node PMNL numbers that remained depressed during Dry Eye Disease. Depressed lymph node PMNL in females correlated directly with decreased LXA4 formation and an early increase in activated CD4+ T cells and dry eye pathogenesis. Importantly, we identified dynamic expression of the LXA4 receptor, ALX, in T cells from draining lymph nodes. These ground breaking findings inspired three specific aims: I. Establish the role of LXA4- producing tissue-PMNL and LXA4 in the ocular surface and draining lymph nodes in immune-driven Dry Eye Disease. II. Elucidate the mechanism for tissue-PMNL and LXA4 receptor (ALX) mediated suppression of effector T cell activation using a novel ALX KO-GFP promoter reporter mouse line. III. Investigate the role of sex steroids in the female specific regulation of LXA4-producing PMNL and identify factors that recruit this novel PMNL population by proteomic and lipidomic approaches. The goals of the project are to investigate the role of tissue-PMNL, LXA4 and its receptors in immune-driven Dry Eye Disease and establish their sex-specific regulation as a significant factor and therapeutic target in aberrant effector T cell activation and initiation of ocular disease in females.
The goal of this project is to investigate the mechanism of action and sex-specific regulation of a novel regulatory PMNL population in the ocular surface and draining lymph nodes that are an important checkpoint system and potential therapeutic target for preventing initiation of immune-driven ocular diseases in females.
|Pazos, Michael A; Lanter, Bernard B; Yonker, Lael M et al. (2017) Pseudomonas aeruginosa ExoU augments neutrophil transepithelial migration. PLoS Pathog 13:e1006548|
|Francos-Quijorna, Isaac; Santos-Nogueira, Eva; Gronert, Karsten et al. (2017) Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury. J Neurosci 37:11731-11743|
|Deguine, Jacques; Wei, Jessica; Barbalat, Roman et al. (2017) Local TNFR1 Signaling Licenses Murine Neutrophils for Increased TLR-Dependent Cytokine and Eicosanoid Production. J Immunol 198:2865-2875|
|Wei, Jessica; Gronert, Karsten (2017) The role of pro-resolving lipid mediators in ocular diseases. Mol Aspects Med 58:37-43|
|Livne-Bar, Izhar; Wei, Jessica; Liu, Hsin-Hua et al. (2017) Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury. J Clin Invest :|
|Rauch, Isabella; Deets, Katherine A; Ji, Daisy X et al. (2017) NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8. Immunity 46:649-659|
|Mozurkewich, Ellen L; Greenwood, Matthew; Clinton, Chelsea et al. (2016) Pathway Markers for Pro-resolving Lipid Mediators in Maternal and Umbilical Cord Blood: A Secondary Analysis of the Mothers, Omega-3, and Mental Health Study. Front Pharmacol 7:274|
|Walter, Scott D; Gronert, Karsten; McClellan, Allison L et al. (2016) ?-3 Tear Film Lipids Correlate With Clinical Measures of Dry Eye. Invest Ophthalmol Vis Sci 57:2472-8|
|Gao, Yuan; Min, Kyungji; Zhang, Yibing et al. (2015) Female-Specific Downregulation of Tissue Polymorphonuclear Neutrophils Drives Impaired Regulatory T Cell and Amplified Effector T Cell Responses in Autoimmune Dry Eye Disease. J Immunol 195:3086-99|