Glucocorticoid‐induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques

Abstract

SummaryGlucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) is the 18th member of the tumour necrosis factor receptor superfamily (TNFRSF18) and is known to interact with its cognate ligand GITRL (TNFSF18). We investigated the potential role of GITR in the pro-inflammatory activation of macrophages. Immunohistochemistry and in situ hybridization analyses of human atherosclerotic plaques demonstrated that GITR and its ligand are expressed mainly in lipid-rich macrophages. We then investigated the role of GITR in human and mouse monocyte/macrophage functions. Stimulation of GITR caused nuclear factor (NF)-jB-dependent activation of matrix metalloproteinase-9 (MMP-9) and pro-inflammatory cytokine expression in both the human and mouse monocytic/macrophage cell lines, THP-1 and RAW264.7, respectively. These cellular responses were also observed when the THP-1 cells were treated with phorbol-12 myristate-13 acetate (PMA), which is known to induce macrophage differentiation. To demonstrate that these responses are not restricted to cultured cell lines, we tested primary macrophages. Both peritoneal and bone marrow-derived macrophages responded to GITR stimulation with induction of MMP-9 and tumour necrosis factor-a (TNF-a). Furthermore, the GITR staining pattern overlapped with those of MMP-9 and TNF-a in atherosclerotic plaques. These data indicate that GITR-mediated macrophage activation may promote atherogenesis via the induction of pro-atherogenic cytokines/chemokines, and destabilize the atherosclerotic plaques via the induction of the matrix-degrading enzyme, MMP-9.

Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related (GITR)-Fc Fusion Protein Inhibits GITR Triggering and Protects from the Inflammatory Response after Spinal Cord Injury

“…In fact, evidence in other experimental models suggests that GITRL can activate cytoplasmic signals in a number of cells, including dendritic cells, where GITRL triggering by GITR inhibits IL-12 production and increases tryptophan catabolism, thus favoring a tolerogenic phenotype that could account for a decreased inflammation Grohmann et al, 2007). Moreover, results in other studies indicate that GITRL triggering on APC promotes inflammatory response (Shin et al, 2003;Kim et al, 2006). In the present experimental model we show that a milder inflammatory response was induced in GITR Ϫ/Ϫ compared with GITR ϩ/ϩ mice, but also that GITR-Fc administration exerted no significative effect in SCI-GITR Ϫ/Ϫ mice but was effective in SCI-GITR ϩ/ϩ .…”

Nutrigenomics in the whole-genome scanning era: Crohn’s disease as example

“…Thus, polymorphisms in HLA-D genes may disrupt this important bridge between the innate and adaptive immune systems. TNFSF15 and TNFS18, members of the tumor necrosis factor (TNF) superfamily, encoding TNFlike 1 and glucocorticoid-induced tumour necrosis factor receptor family-related protein ligand, respectively, are proinflammatory cytokines whose effects are mediated through NF-kB activation, via pathways similar to TLRs and NOD2 [68,69]. TNF-a induced protein 3 (TNFAIP) inhibits NF-kB activation [70] driven by TNF-a, and other TFNSF members [71].…”

Lymphocytic tumor necrosis factor receptor superfamily co-stimulatory molecules in the pathogenesis of atherosclerosis

“…Increased sOX40 levels in patients with unstable angina [33] Polymorphisms in TNFSF4 gene correlate with myocardial infarction in women [30] GITRL GITR Uncertain Expression of GITR(L) in atherosclerotic plaque intima [34] Decreased number of GITR þ Treg cells in atherosclerotic lesions [35] CD30L CD30 Atherogenic -shown by administration of CD30L-antibody [36…”