Abstract

Innate lymphoid cells (ILCs) have emerged as largely tissue-resident archetypal cells of the immune system. We tested the hypotheses that renal ischemia-reperfusion injury (IRI) is a contributing factor to polarization of ILCs and that glucocorticoid-induced leucine zipper (GILZ) and cannabidiol regulate them in this condition. Mice subjected to unilateral renal IRI were treated with the following agents before restoration of renal blood flow: cannabidiol, DMSO, transactivator of transcription- (TAT-) GILZ, or the TAT peptide. Thereafter, kidney cells were prepared for flow cytometry analyses. Sham kidneys treated with either cannabidiol or TAT-GILZ displayed similar frequencies of each subset of ILCs compared to DMSO or TAT, respectively. Renal IRI increased ILC1s and ILC3s but reduced ILC2s compared to the sham group. Cannabidiol or TAT-GILZ treatment of IRI kidneys reversed this pattern as evidenced by reduced ILC1s and ILC3s but increased ILC2s compared to their DMSO- or TAT-treated counterparts. While TAT-GILZ treatment did not significantly affect cells positive for cannabinoid receptors subtype 2 (CB2+), cannabidiol treatment increased frequency of both CB2+ and GILZ-positive (GILZ+) cells of IRI kidneys. Subsequent studies showed that IRI reduced GILZ+ subsets of ILCs, an effect less marked for ILC2s. Treatment with cannabidiol increased frequencies of each subset of GILZ+ ILCs, but the effect was more marked for ILC2s. Indeed, cannabidiol treatment increased CB2+ GILZ+ ILC2s. Collectively, the results indicate that both cannabidiol and GILZ regulate ILC frequency and phenotype, in acute kidney injury, and that the effects of cannabidiol likely relate to modulation of endogenous GILZ.

Highlights

  • Dysregulation of immune and inflammatory mechanisms contributes importantly to pathogenesis of a variety of disorders including acute kidney injury (AKI) [1,2,3]

  • We recently showed that both glucocorticoidinduced leucine zipper (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]

  • While ILC1s and ILC3s of cannabidiol-treated IRI kidneys remained higher than sham-operated kidneys, no difference was noted in ILC2s between cannabidiol-treated IRI kidneys and sham-operated kidneys (Figures 1(b)–1(d))

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Summary

Introduction

Dysregulation of immune and inflammatory mechanisms contributes importantly to pathogenesis of a variety of disorders including acute kidney injury (AKI) [1,2,3]. Glucocorticoids have been used for diverse disorders with the common denominator of dysregulation of immune and inflammatory mechanisms [4]. Recognition of their adverse metabolic effects has prompted unraveling of mechanisms which contribute to their prominent antiinflammatory effects. These studies have provided strong evidence in favor of glucocorticoid-induced leucine zipper (GILZ) protein as the pivotal regulator of anti-inflammatory effects of glucocorticoids [5,6,7]. Therapeutic GILZ has raised the prospect of curtailing pathogenic inflammation while avoiding adverse metabolic effects of glucocorticoids

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