GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation. (July 2015)

• Record Type: Journal Article
• Authors: Jones, Sarah A.; Perera, Diluptha N.; Fan, Huapeng; Russ, Brendan E.; Harris, James; Morand, Eric F.
• Is Part Of: Journal of autoimmunity. Volume 61(2015)
• Page Start: 73
• Page End: 80
• Publication Date: 2015-07
• Subjects: Glucocorticoid-induced leucine zipper -- GILZ -- Th17 -- IL-17 -- Glucocorticoid -- Psoriasis; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.05.010
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Patients with inflammatory autoimmune diseases are routinely treated with synthetic glucocorticoids to suppress immunopathology. A crucial outcome of glucocorticoid exposure is induction of glucocorticoid-induced leucine zipper (GILZ), a protein with multiple functions that include inhibition of key immune cell signalling pathways. Here we report that GILZ maintains a threshold for activation of Th17 responses and IL-17-dependent pathology. GILZ expression was deficient in lesional skin of psoriasis patients and was negatively correlated with the pro-inflammatory cytokines IL-23, IL-17A and IL-22, and with STAT3 expression. Deficiency of GILZ in mice resulted in excessive inflammation and pro-inflammatory cytokine expression in the imiquimod model of psoriasis, and dendritic cells lacking GILZ produced greater IL-1, IL-23 and IL-6 in response to imiquimod stimulation in vitro . These cytokines stimulate Th17 cell differentiation, and we found unchallenged GILZ-deficient mice to have spontaneous production of IL-17A and IL-22 in vivo. We also identified a T cell-intrinsic role for GILZ in limiting Th17 cell formation in vitro in response to Th17-promoting cytokines IL-1β and IL-23. Addition of IL-6 under these conditions suppressed GILZ, allowing T cell proliferation and expression of Th17 genes, whereas exogenous delivery of GILZ using a cell-permeable fusion protein restored regulation of Th17 cell proliferation. Thus, GILZ has a non-redundant function to constrain pathogenic Th17 responses, with clinical implications for psoriasis. Highlights: GILZ is an anti-inflammatory glucocorticoid-induced protein expressed in T cells. GILZ is reduced in psoriatic skin, correlated with increased IL-17, IL-22, IL-23. GILZ deficiency worsens IL-17-mediated skin inflammation in mice. IL-6 down-regulates GILZ and promotes robust Th17 responses. Treatment of Th17 cells with cell-permeable GILZ restores regulation.