Date of Award

Summer 2022

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Mitzi Nagarkatti

Second Advisor

Prakash Nagarkatti

Abstract

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) arises from pulmonary inflammatory diseases that stem from direct and indirect activation of immune cells. Severe complications from ALI/ARDS arise when inflammatory mediators initiate an overzealous immune response leading to the destruction of lung epithelial cell barriers, which causes systematic oxygen deprivation. Infiltrating innate immune cells drive the immune response during the acute phase of a lung injury. However, I3C, a naturally occurring AhR ligand found in cruciferous vegetables such as broccoli, collard greens, and kale, plays a crucial role in suppressing inflammatory mediators through its immunomodulatory functionality, which regulates both innate and adaptative immune cells.

Our first study characterized the chemokines and chemokine receptors associated with the recruitment of myeloid cell subsets during the LPS-induced ARDS mice model. Our second study focused on the migration relationship of pro-inflammatory CCR2+ monocytes and CXCR2+ neutrophils during lung injury and the effects I3C had on their recruitment. We found that I3C decreased the frequency of infiltrating pro-inflammatory CCR2+ monocytes during lung injury, which induced a downshift in the recruitment of CXCR2+ neutrophils to diseased lungs.

The final study identified that I3C protects lung structure integrity during ALI through the downshift of pathogenic Th17 cells and upshift of tissue maintenance Th22 cells. In addition, miRNA play a critical role in regulating gene expression especially those that regulate immune response. We observed that treatment with I3C significantly altered the expression of several miRNAs directly or indirectly targeting IL-22 and RORc, the gene for RORγT. Notably, after testing the several miRNAs targeting RORc, AhR, and IL-22 genes, only miR-29b-2-5p, a miRNA in the miR-29b-5p family, was validated to target genes associated with Th17 and Th22 cells. The dysregulation of miR-29b-2-5p is speculated to be responsible for the Th17/Th22 shift.

Taken together, our studies demonstrate that I3C immunomodulatory functionality can regulate the myeloid cells' inflammatory response and recruitment during lung inflammation while protecting the lung epithelial structure through the modulation of adaptive immune cells. Therefore, a diet consisting of I3C may serve as a therapeutic for ARDS.

Rights

© 2022, Bryan Latrell Holloman

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