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Growth factors, cytokines, and cell cycle molecules
G-CSF and Neutrophils Are Nonredundant Mediators of Murine Experimental Autoimmune Uveoretinitis

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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.

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Supported by The Ophthalmic Research Institute of Australia, CSL Limited and Reid Charitable Trusts, The National Health and Medical Research Council (Canberra, Australia), Career Development Fellowship grant 1034598 (G.L.G.), Peter Doherty Post-Doctoral Fellowship grant 310608 (A.L.C.), Industry Research Fellowship grant 461287 (I.K.C.), Clinical Practitioner Fellowship grant 1023407 (I.P.W.), program grant 1016647 (I.P.W.), and operational infrastructure grants through the Australian Government Institute for Research and Innovation in Social Services and the Victorian State Government Offer Information Statement.

Disclosures: CSL limited has a commercial interest in the development of cytokine antagonists and provided partial funding for the project. I.K.C., K.S.-I., B.S.M., and E.M. are employees of CSL limited, own stock, and/or have stock options in CSL limited. I.P.W. and I.K.C. are inventors on a patent covering granulocyte colony-stimulating factor antagonism that has been licensed to CSL limited.