Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury

Abstract

The glucocorticoid-induced leucine zipper (GILZ) mediates antiinflammatory effects of glucocorticoids. Acute kidney injury (AKI) mobilizes immune/inflammatory mechanisms, causing tissue injury, but the impact of GILZ in AKI is not known. Neutrophils play context-specific proinflammatory [type 1 neutrophil (N1)] and anti-inflammatory [type 2 neutrophil (N2)] functional roles. Also, regulatory T lymphocytes (Tregs) and regulatory T-17 (Treg17) cells exert counterinflammatory effects, including the suppression of effector T lymphocytes [e.g., T-helper (Th) 17 cells]. Thus, utilizing cell preparations of mice kidneys subjected to AKI or sham operation, we determined the effects of GILZ on T cells and neutrophil subtypes in the context of its renoprotective effect; these studies used the transactivator of transcription (TAT)-GILZ or the TAT peptide. AKI increased N1 and Th-17 cells but reduced N2, Tregs, and Treg17 cells in association with increased interleukin (IL)-17 1 but reduced IL-10 1 cells accompanied with the disruption of mitochondrial membrane potential (c m ) and increased apoptosis/necrosis compared with sham kidneys. TAT-GILZ, compared with TAT, treatment reduced N1 and Th-17 cells but increased N2 and Tregs, without affecting Treg17 cells, in association with a reduction in IL-17 1 cells but an increase in IL-10 1 cells; TAT-GILZ caused less disruption of c m and reduced cell death in AKI. Importantly, TAT-GILZ increased perfusion of the ischemicreperfused kidney but reduced tissue edema compared with TAT. Utilizing splenic T cells and bone marrow-derived neutrophils, we further showed marked reduction in the proliferation of Th cells in response to TAT-GILZ compared with response to TAT. Collectively, the results indicate that GILZ exerts renoprotection accompanied by the upregulation of the regulatory/suppressive arm of immunity in AKI, likely via regulating cross talk between T cells and neutrophils.

Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis

“…According to the National Health Commission of China's Diagnosis and Treatment of New Coronavirus Pneumonia guidelines [22], glucocorticoids, lopinavir/ritonavir, and ribavirin are treatment options for COVID-19. Interestingly, glucocorticoids provide a renoprotective effect in AKI via glucocorticoidinduced leucine zipper-(GILZ-) induced immunosuppression [66]. In contrast, lopinavir/ritonavir is widely used to treat AIDS and has been reported to cause renal tubular dysfunction and CKD [67].…”

Regulation of Innate Lymphoid Cells in Acute Kidney Injury: Crosstalk between Cannabidiol and GILZ

“…Thus, there is a need to identify therapeutic options that can modulate ILC subsets to those of the normal kidney with the objective of conferring beneficial impact to the ischemic-reperfused kidney. In light of our recent demonstration that both cannabidiol and GILZ exert significant renoprotective effects, as reflected by reduction in cell death and improved functional outcomes, in association with similar changes in polarization of neutrophils and T lymphocytes in favor of their regulatory/suppressive phenotypes [16,17], we sought to establish the impact of each agent on the profile of ILC subsets of the kidney subjected to IRI. Interestingly, cannabidiol and GILZ caused similar changes in the profile of ILC subsets in the ischemic-reperfused kidney, restoring their levels towards those of sham-operated kidneys.…”

“…in preparation for the surgical procedure which consisted of two flank incisions and clamping of the left renal pellicle, for 20 min, using a nontraumatic vascular clamp while the right kidney served as sham control. Thereafter, the vascular clamp was removed and restoration of renal Journal of Immunology Research blood flow confirmed, visually, prior to closure of muscle and skin layers using 4-0 silk sutures and autoclips, respectively [16,17]; each independent experiment included 3-6 animals, and the number of animals for each group/condition is indicated under Figure legends. Each of the following agents was administered, intraperitoneally in a volume of 50 μl, 10 min before restoration of renal blood flow: (a) vehicle (DMSO), (b) cannabidiol (10 mg/kg, 16), (c) TAT (0.1 mg/kg in PBS), and (d) TAT-GILZ (0.2 mg/kg in PBS); the latter dosage regimen is based on a two-fold larger molecular weight of GST-TAT-GILZ than GST-TAT as well as studies indicating resolution of LPS-induced inflammation in response to TAT-GILZ treatment and its effectiveness in the murine model of acute kidney injury [17,29].…”

“…We recently showed that both GILZ and cannabidiol exert renoprotective effects, as reflected by reduction in cell death and improved functional outcomes, in the murine model of AKI simulated by ischemia-reperfusion injury (IRI); the renoprotection of GILZ and cannabidiol was accompanied with generally similar effects of each agent on polarization of neutrophils and T lymphocytes [16,17]. In light of these observations, we decided to explore potential impact of cannabidiol and GILZ on innate lymphoid cells (ILCs) in AKI.…”

“…Thus, an interaction between these receptor subtypes in regulation of ILCs cannot be ruled out. Importantly, while we have focused on studying ILCs, our recent demonstration that cannabidiol and GILZ exert similar effects on polarization of both neutrophils and T lymphocytes [16,17] raises the possibility of similar crosstalk between cannabidiol and GILZ in regulation of regulatory/suppressive phenotypes of cells of both innate and adaptive immunity. Collectively, our observations provide a plausible explanation for previously reported similarities between the endocannabinoid system and glucocorticoids in regulation of immune and inflammatory processes [8].…”