G-CSF and Neutrophils Are Nonredundant Mediators of Murine Experimental Autoimmune Uveoretinitis

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a regulator of neutrophil production, function, and survival. Herein, we investigated the role of G-CSF in a murine model of human uveitis-experimental autoimmune uveoretinitis. Experimental autoimmune uveoretinitis was dramatically reduced in G-CSF-deficient mice and in anti-G-CSF monoclonal antibody-treated, wild-type (WT) mice. Flow cytometric analysis of the ocular infiltrate in WT mice with experimental autoimmune uveoretinitis showed a mixed population, comprising neutrophils, macrophages, and T cells. The eyes of G-CSF-deficient and anti-G-CSF monoclonal antibody-treated WT mice had minimal neutrophil infiltrate, but no change in other myeloid-derived inflammatory cells. Antigen-specific T-cell responses were maintained, but the differentiation of pathogenic type 17 helper T cells in experimental autoimmune uveoretinitis was reduced with G-CSF deficiency. We show that G-CSF controls the ocular neutrophil infiltrate by modulating the expression of C-X-C chemokine receptors 2 and 4 on peripheral blood neutrophils, as well as actin polymerization and migration. These data reveal an integral role for G-CSF-driven neutrophil responses in ocular autoimmunity, operating within and outside of the bone marrow, and also identify G-CSF as a potential therapeutic target in the treatment of human uveoretinitis.

Neutrophils in animal models of autoimmune disease

“…In the absence of G-CSF, inflammation and neutrophil accumulation is decreased. In line with this finding, anti-G-CSF antibody treatment also suppresses the intraocular inflammation [79]. As in other autoimmune models, the potential roles of G-CSF in EAU include mobilization of neutrophils from the bone marrow, triggering neutrophil-attracting chemokines from tissue resident cells and upregulating the chemokine receptor CXCR2 on the cell surface of neutrophils [79].…”

“…ankylosing spondylitis, Behcet’s disease, etc.) and is the leading cause of blindness in Western societies [79]. Experimental autoimmune uveoretinitis (EAU) can be triggered in mice by immunization with the interphotoreceptor retinoid-binding protein (IRBP).…”

“…Experimental autoimmune uveoretinitis (EAU) can be triggered in mice by immunization with the interphotoreceptor retinoid-binding protein (IRBP). Wild type mice develop leukocytosis with marked neutrophilia in EAU that correlates with increased G-CSF levels in the serum and the eye [79]. In the absence of G-CSF, inflammation and neutrophil accumulation is decreased.…”

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

“…The clinical use of G-CSF for the recovery of neutrophil number and function in chemotherapy patients has also revealed critical toxicities, notably neutrophil-induced pulmonary toxicity, alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis (59,60). Accordingly, recent research into G-CSF points to it as a therapeutic target in diseases where G-CSF and/or the activity of neutrophils is pathogenic (23)(24)(25).…”

“…G-CSFdeficient mice are neutropenic and also exhibit reduced numbers of bone marrow myeloid precursors (20), and while they are susceptible to acute bacterial infection (21), they handle chronic bacterial infection (22). More recent studies have shown that despite G-CSF's role in innate immunity, G-CSF has pathogenic roles in inflammatory autoimmune diseases such as inflammatory arthritis (23), experimental allergic encephalomyelitis (24), and uveoretinitis (25). Furthermore, G-CSF is induced in airway inflammation and in response to cigarette smoke (26)(27)(28)(29), but its role in COPD and its complex comorbidome has not been investigated.…”