Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis

Abstract

Overexpression of the constitutive chemokine receptor CXCR4 has been shown to contribute to the accumulation of leukocytes at sites of chronic inflammation. Glucocorticoids are widely used to treat inflammatory disorders such as uveitis to considerable effect, yet paradoxically have been reported to increase CXCR4 expression in vitro. We show here that ocular lymphocytes isolated from patients with uveitis who had been treated with topical glucocorticoids expressed highly elevated levels of CXCR4. The up-regulation of CXCR4 could be reproduced in vitro by culture of CD4+ T cells with aqueous humor (AqH), indicating a role for the ocular microenvironment rather than preferential recruitment of CXCR4+ cells. Untreated uveitis and noninflammatory AqH up-regulated CXCR4 to a limited extent; this was dependent on TGF-β2. However, the highest levels of CXCR4 both in vivo and in vitro were found in the glucocorticoid-treated patients. Glucocorticoids appeared to be directly responsible for the induction of CXCR4 in treated patients, as the glucocorticoid receptor antagonist RU38486 inhibited the in vitro up-regulation by AqH from these patients. Dexamethasone selectively up-regulated CXCR4 in vitro, but not any of a wide range of other chemokine receptors. CXCL12, the ligand for CXCR4, was present in AqH under noninflammatory conditions, but the levels were low in untreated uveitis and undetectable in treated uveitis AqH. The importance of these results for the treatment of HIV patients with glucocorticoids is discussed as well as a role for glucocorticoid-induced CXCR4 up-regulation and CXCL12 down-regulation in controlling the migration of lymphocyte populations, resulting in resolution of inflammation.

Stromal Cell-Derived Factor-1 Is Essential for Photoreceptor Cell Protection in Retinal Detachment

“…14 In addition, SDF-1/CXCR4 potentially mediates ocular inflammation by recruiting CD4 ϩ T-cells, and is potentially involved in the formation of proliferative membranes in eyes with proliferative vitreoretinopathy. 15,16 Therefore, interest in understanding the role of SDF-1/CXCR4 in non-neovascular inflammatory or proliferative ocular diseases remains great.…”

Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck

“…13,14,33 There have been several reports demonstrating that GCs and DM can directly up-regulate CXCR4 expression in monocytes and T lymphocytes, resulting in an increased capacity of these cells to migrate in response to CXCL12. 13,14,33 However, in those published studies, GC treatment required more extensive incubation times (up to 16 hours) before any effects on CXCR4 expression could be observed. In contrast, our DM effects on cell migration were observed as early as 5 minutes after DM treatment, with optimal effects on migration being noted at the 2-hour time interval, which failed to demonstrate any change in CXCR4 cell surface expression on primary human T cells or Jurkat cells ( Figure S5A).…”

Blockade of CXCL12/CXCR4 Axis Ameliorates Murine Experimental Colitis

“…Recent studies showed that this chemokine axis is also involved in several inflammatory diseases, including rheumatoid arthritis (Nanki et al, 2000;Tamamura et al, 2004;Haas et al, 2005), inflammatory liver diseases (Terada et al, 2003;Wald et al, 2004), uveitis (Curnow et al, 2004), and pulmonary fibrosis (Phillips et al, 2004). Nanki et al (2000) reported that memory T cells highly express CXCR4, and the CXCL12 concentration is extremely high in the synovial fluid of patients with rheumatoid arthritis.…”