A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

Abstract

IFN-γ stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN-γ stimulation because of a requirement for autocrine TNF-α signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55−/− mice stimulated with IFN-γ. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN-γ activation are controlled by autocrine secretion of TNF-α, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors.

Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice

“…It was also demonstrated that TNF-␣ provoked inflammatory responses (37). TNF p55 receptor-deficient mice were resistant to EAU (38). These previous studies (32) appeared to be consistent with our present observations.…”

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] ).…”

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

“…IFN-induces macrophage activation and nitric oxide production, which leads to destruction of retina in EAU (Hoey et al 1997). TNF- provokes inflammatory responses (Green and Flavell 1999) and TNF p55 receptor deficient mice are resistant to EAU (Calder et al 2005).…”