The effect of endogenous and exogenous glucocorticoids acting through regulatory T cells on resolution of ALI and the contribution of host genetic variability.

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Project Summary Critical questions remain regarding the recovery of lung structure and function following acute respiratory distress syndrome (ARDS) and pneumonia. A subset of immune cells, Foxp3+ regulatory T lymphocytes (Tregs), are essential in resolving inflammation for several experimental models of acute lung injury (ALI). Furthermore, several groups, including ours, have established that Tregs are present in the lungs of patients with ARDS, suggesting Tregs contribute to recovery during ARDS. While therapies are limited for ARDS, several trials have illustrated the mortality benefits of glucocorticoid (GC) therapy for ARDS and pneumonia. The mechanistic effects of GC are pleiotropic, and their influences on Treg phenotype and function are varied and remain ill- defined during ARDS. Furthermore, the heterogeneity of patient responses to GC and the contribution of the etiology and severity of the illnesses, the timing of therapy, and the dosage of GC to GC's efficacy all merit more investigation. Our published studies in murine ALI demonstrate that during the resolving phase of lung injury, Tregs expand in number and change their gene expression profiles compared to Tregs in uninjured control lungs. Treg transcriptome profiles suggest changes in gene expression that may contribute to Treg-driven lung repair. One transcript upregulated in Tregs isolated from resolving lung tissue is the glucocorticoid receptor (GR) (Nr3c1). Our Aims seek to test the hypothesis that glucocorticoid signaling occurs through Tregs, and this Treg- signaling is critical to GC effects. Aim 1 proposes to determine the function of Treg’s GR signaling and the direct and indirect impact of GCs on Treg-promoted resolution. We hypothesize that the administration of exogenous GC affects Treg responses during resolution. Additionally, we will test the hypothesis that GR-deficient Tregs have decreased immunomodulatory and tissue reparative effects during ALI. Aim 2 addresses the effects of host genetic variations on the functions of Tregs and the effects of GCs. Host genetic variation likely impacts on the immunologic response during ARDS and are determinants of outcomes. The Collaborative Cross (CC) is a multi- parental genetic reference population generated using eight founder mouse strains. These genetically diverse CC strains demonstrate phenotypic variability useful for genetic mapping disease trait-associated quantitative trait loci (QTL). Variation in Treg phenotypes in the CC has been reported. Aim 2 proposes leveraging the CC's genetic diversity to test the hypotheses that 1) host genetic variation impacts the response to exogenous GC administration after inducing ALI and 2) variation in the Treg number or effector phenotypes across the CC associates with different rates of resolution of ALI and identifies genetic loci that define genes of host variation. We predict that the proposed studies will identify genetic loci that modulate Treg responses critical in resolving ALI and will identify the role of GCs in promoting resolution. Identifying and elucidating these mechanisms of GC action and GR function may identify possible therapeutic approaches to lessen collateral tissue damage without negatively altering the response to injury.