GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus.

Champa Nataraja,Mehnaz Pervin,Jacqueline Flynn,Megan A Cristofaro,Sarah A Jones,Eric F Morand,Wendy Dankers,Fabien B Vincent,Joshua Ooi,James Harris,Wendy Zhu,Linden J Gearing,Rochelle Sherlock,Jacinta P W Lee,Md Abul Hasnat

doi:10.3389/fimmu.2021.652800

Abstract

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn-/-) mice in which GILZ expression was genetically ablated. In Lyn-/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A, and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18. This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE.

Highlights

Glucocorticoid-induced leucine zipper (GILZ) exhibits a range of anti-inflammatory effects that invites significant interest as a potential target in developing an alternative therapeutic to glucocorticoids
A detailed analysis of the microorganisms detected within sentinel animals in the same room in which our colonies were housed in shown in Supplemental Figure 1, we did not test whether the changes impacted on the development of an autoimmune phenotype in the GILZ-/- strain
This detailed kinetic study of the degree of splenomegaly confirms that GILZ deficiency is permissive of the development of autoimmunity triggered by underlying genetic factors

Summary

Introduction

Glucocorticoid-induced leucine zipper (GILZ) exhibits a range of anti-inflammatory effects that invites significant interest as a potential target in developing an alternative therapeutic to glucocorticoids. We have previously shown that GILZ is a non-redundant regulator of B cell activity, with GILZ deficiency resulting in heightened B cell activation and proliferation which was reversed by treatment with a cell-permeable GILZ fusion protein [12]. These findings have important clinical correlates, for example, GILZ induction by glucocorticoids in most B cell subsets was negatively correlated with SLE disease activity [12]. Others have independently confirmed that GILZ mRNA expression is negatively correlated with the SLE disease activity index (SLEDAI) [13, 14]

Methods

Results

Conclusion