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Mary J Mattapallil, Yingyos Jittayasothorn, Zhijian Wu, H Nida Nida Sen, Rachel R Caspi; Interleukin-34 provide neuroprotection to the neural retina in a mouse model of experimental autoimmune uveoretinitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2535.
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© ARVO (1962-2015); The Authors (2016-present)
Interleukin-34 (IL-34) is a novel cytokine primarily produced by neuronal cells and induces differentiation, survival and proliferation of macrophages, monocytes, and microglia under inflammatory conditions. Increased levels of IL-34 have been reported in patients with various autoimmune diseases and correlate positively with levels of pro-inflammatory cytokines. However, IL-34 has also been shown to induce Foxp3+ T regulatory cells through M2 polarization of monocytes. Since retina contains both neuronal and (macrophage-like) microglial cells, we examined the role of IL-34 in autoimmune uveitis using the mouse model of Experimental Autoimmune Uveitis (EAU).
Levels of IL-34 and other pro-inflammatory cytokines were analyzed in serum samples from uveitis patients and healthy controls. EAU was induced in C57BL/6J mice by immunization with retinal antigen and expression of IL-34 and its receptors were determined in various retinal cells during the course of EAU. IL-34 was neutralized or overexpressed locally by intraocular injection of neutralizing antibody or subretinal injection of Adeno Associated Vector serotype 8 (AAV8), respectively, in mice immunized for EAU.
Detectable levels of IL-34 were present in sera of Uveitis patients and some healthy controls. In mice, retinal photoreceptor cells and retinal glial Müller cells constitutively expressed IL-34 cytokine whereas its receptors, Csf1r and Ptpr-b were expressed by retinal microglial cells and by photoreceptors, respectively. Expression of IL-34 in the mouse retina gradually decreased with progression of EAU disease. Importantly, local overexpression of IL-34 within the eye completely protected the neural retina from damage due to autoimmune uveitis.
Locally produced IL-34 has a role in neuroprotection. During autoimmune uveitis, gradual degeneration of retinal photoreceptor layer could deplete endogenous production of IL-34. Local overexpression of IL-34 by gene therapy can compensate for loss of endogenous IL-34 production resulting in protection of neural retina from autoimmune inflammatory challenge. Future studies will address the molecular mechanisms involved in this process. Our finding suggest that IL-34 could offer a promising treatment strategy to enhance neuroprotection in a wide spectrum of sight-threatening autoimmune uveitic diseases.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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