TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis

Abstract

Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b+ macrophages and CD4+ T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b+ myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-γ and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-γ and autocrine TNF-α signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction.

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…In support, we observe that tissue damage in experimental retinal inflammation is significantly attenuated when macrophages are removed 21,22 or macrophage/monocyte activation is blocked. 16,[23][24][25] Experimentally, we observe that the tissue is protected when TNF-alpha activity is neutralised (and indeed show the requisite requirement of TNF for macrophage activation in ocular inflammation [26][27][28] ), or by reprogramming macrophage activation threshold with CD200R treatment. These consistent observations have led to a pipeline for therapeutic opportunities to redress activation thresholds of immune cells.…”

“…43,44 In EAU, both Th1 and Th17 T helper cells are important inducers of autoimmune disease. 35,45 It is the cytokines (especially IFN-γ produced by Th1 cells) produced by these cells that activate the non-specific mononuclear tissue infiltration (principally macrophages) and recruit neutrophils as seen in EAU (eg, through interleukin (IL)-17 produced from Th17 cells 7,8,23,24,[26][27][28] ).…”

TNFR1 signalling is a critical checkpoint for developing macrophages that control of T‐cell proliferation

“…We have demonstrated that the Mu that accumulate in the target organ modify T cell responses, suppressing T cell proliferation but preserving cytokine secretion. 10 These Mu express cell surface markers such as Gr1 and CD31 that are associated with immune regulation, and to investigate the function of such cells, we generated Mu in vitro from BM cells cultured in an inert environment (hydrophobic PTFEcoated tissue culture bags). We compared the ability of these cells to present antigen with other APCs.…”

“…[5][6][7] In this environment, the large majority of CD11b + cells are usually described as macrophages (Mu); they release inflammatory mediators and act as professional antigen-presenting cells (APCs). [8][9][10] They can stimulate autoantigen-specific CD4 + T cells, by presenting MHC class II-restricted peptides and we have recently reported that Mu derived from the inflamed retina of mice with EAU can act as myeloid regulatory cells, inhibiting T-cell proliferation while allowing normal antigenspecific T-cell cytokine production. 10 One important cytokine produced by activated Mu is tumour necrosis factor-a (TNF-a) and the expression of one of its receptors, TNFR1, is necessary for the normal development of organ-specific autoimmunity.…”

“…[8][9][10] They can stimulate autoantigen-specific CD4 + T cells, by presenting MHC class II-restricted peptides and we have recently reported that Mu derived from the inflamed retina of mice with EAU can act as myeloid regulatory cells, inhibiting T-cell proliferation while allowing normal antigenspecific T-cell cytokine production. 10 One important cytokine produced by activated Mu is tumour necrosis factor-a (TNF-a) and the expression of one of its receptors, TNFR1, is necessary for the normal development of organ-specific autoimmunity. 11,12 Blocking signals through this receptor produces a number of important changes in Mu function, including the abro-…”