Myeloid-Specific ARNT Signaling Drives Sex-Based Differences in Acrolein-Induced Pulmonary Toxicity
This dissertation investigates the role of myeloid-specific ARNT in modulating the pulmonary immune response to acrolein, a highly reactive environmental toxicant. Using a murine model with myeloid-specific overexpression of Arnt-a (homolog of human ARNT isoform 1), this study characterizes both the both the initiation (24-hours) and resolution (5-day) phases of acrolein-induced acute lung injury, incorporating both sex and age as key biological variables and potential determinants of the severity of the response. At the 24-hour timepoint, single-cell RNA sequencing, bronchoalveolar lavage (BAL) cytokine profiling, and immune cell phenotyping revealed that female Arnt-a transgenic mice exhibited attenuated neutrophilic inflammation, reduced proinflammatory cytokine expression, and accumulation of FOXP3+ regulatory T cells. In contrast, Arnt-a transgenic males uniquely recruited myeloid-derived suppressor cells to the lung, indicating divergent immunomodulatory responses. To assess the impact of ARNT overexpression on inflammatory resolution, BAL cell counts, serum cytokine analysis, and lung histology were performed 5 days post-exposure. Arnt-a overexpression facilitated a more efficient clearance of neutrophils and restored alveolar architecture in 12–20-week male mice. However, females in this age group exhibited persistent inflammation and epithelial damage at this later timepoint, suggesting that Arnt-a may drive a delayed proinflammatory response in females, noticeable at 5 days. These findings underscore the context-dependent effects of ARNT signaling on myeloid cell function and pulmonary inflammation. Collectively, this work identifies ARNT as a key regulator of the immune response to inhaled toxicants and provides novel insights into the transcriptional and physiological mechanisms underlying sex- and age-based differences in recovery from acute lung injury.
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The University of Texas Medical Branch at Galveston