Autoimmune neurologic diseases
Interleukin-34 is a novel cytokine produced primarily by neuronal cells that promotes 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). 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 whereas its receptors, Csf1r and Ptpr-b, were expressed by retinal microglia and by photoreceptors, respectively. Expression of IL-34 in the mouse retina gradually decreased with progression of EAU. Importantly, local overexpression of IL-34 within the eye by adenoviral gene transfer completely protected the neural retina from EAU damage. We conclude that locally produced IL-34 has a role in inhibiting inflammation and enhancing neuroprotection, through still unknown mechanisms. We propose that, during autoimmune uveitis inflammation and/or breakdown of blood-retinal barrier inhibits production and or causes loss of endogenous IL-34. Overexpression of IL-34 by gene transfer restores ocular levels of IL-34, resulting in protection. Our findings suggest that IL-34 could offer a treatment strategy in a wide spectrum of sight-threatening neurodegenerative and inflammatory ocular conditions.