Abstract
Purpose :
Interleukin-34 (IL-34), a cytokine highly expressed in the central nervous system, is reported to have pleiotropic effect on autoimmune and neurodegenerative diseases by regulating myeloid cells. Given that (i) the potential target cell populations of IL-34 in the uveitic eye are resident microglia and infiltrating myeloid cells from the periphery, and (ii) these cell populations are known to play a crucial role in neuroinflammation, we examined the role of IL-34 in the pathogenesis of Experimental Autoimmune Uveitis (EAU) in mice.
Methods :
EAU was actively induced in the C57BL/6J wild type (WT) and IL-34 knockout (IL-34 KO) mice with retinal antigen IRBP651-670. Severity of disease was assessed by fundus examination. Immune cells in the eye, spleen and draining lymph nodes (DLN) were profiled by flow cytometry. Spleen and DLN cells were used for ex vivo proliferation assay and ELISA. EAU was adoptively transferred to naïve recipient mice by infusion of antigen activated lymphocytes from donor EAU mice.
Results :
Severity of EAU was dampened in EAU-immunized IL-34 KO mice, with reduced T cell infiltration into the eye. Absolute numbers of T cells and their effector phenotypes (Th1, Th17 and Treg), as well as number and MHC class II expression of myeloid cells in spleen and DLN were similar in immunized WT and KO mice. There were also no significant differences in the antigen-elicited lymphocyte proliferation and cytokine production in culture between the two strains. Finally, adoptive transfer of in vitro activated lymphocytes from immunized WT donor mice elicited milder EAU in IL-34 KO recipients, suggesting that host-derived IL-34 promotes the effector phase of disease.
Conclusions :
We propose that IL-34 promotes EAU pathogenesis locally in the eye, possibly through effects on resident and/or infiltrating myeloid cells, without affecting antigen-specific T cell priming in the periphery. Future studies will delineate the mode of action of IL-34 by using mice with IL-34 deficiency in the neuronal compartment, and by profiling the transcriptome of eye-resident cells and infiltrating immune cells by scRNA-seq.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.