A109-14 Type 2 Innate Immunity Promotes the Development of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Abstract Hermansky-Pudlak syndrome (HPS) is a group of inherited autosomal recessive disorders caused by genetic mutations that alter the trafficking of lysosomal-related organelles. In patients with HPS types 1 and 4, pulmonary fibrosis develops in the fourth or fifth decade of life and is the major cause of morbidity and mortality. However, the mechanisms that mediate the development of pulmonary fibrosis in HPS have not been completely elucidated. The pale ear mouse, which carries a null mutation of the HPS1 gene, exhibits many features of the human HPS-1 disease phenotype. These mice show exaggerated injury responses and fibroproliferative repair when exposed to fibrogenic agents like bleomycin. Studies by us and others have extensively used the HPS1-bleomycin model to explore how defective protein trafficking contributes to injury and fibrosis. Our studies demonstrate that Type II innate lymphoid cells (ILC2s) play a key role in promoting fibroproliferative repair in HPS. Unlike HPS-1 patients, HPS1-/- mice don’t develop spontaneous lung fibrosis. Despite compelling evidence suggesting that the immune system is integral to HPS pathogenesis, HPS mouse models are typically studied in ultra-hygienic specific pathogen-free (SPF) environments that lack the naturally occurring microbes needed to prime and mature the immune system. These SPF mice have sharply lower numbers of differentiated effector T-cells, innate lymphoid cells, and other myeloid cells, potentially missing critical interactions between a fully matured immune system and pathological features of HPS. Therefore, studying HPS1-/- mouse model in environments that mirror human-like microbial exposure and immunity (referred to here as a “dirty” environment) could lead to valuable fundamental and translational discoveries. Our findings demonstrate that the “dirty” mouse approach successfully matures the immune system in SPF mice through natural microbial exposure. In this setting, “dirty” HPS1-/- mice develop spontaneous lung fibrosis, accompanies by increased ILC2 activation. Importantly, depleting the commensal microbiome/mycobiome using targeted antibiotics and antifungals markedly reduced ILC2 activation and attenuated lung fibrosis in HPS1-/- mice under “dirty” conditions. These results underscore the microbiome/mycobiome’s critical role in modulating immune responses and fibrosis progression in HPS. In conclusion, our study highlights the pivotal role of the gut-lung axis and type 2 innate immunity in HPS-associated fibrosis. Modulating the microbiome presents a promising approach to mitigate fibrosis in HPS patients. These findings offer new insights into the interplay between host immunity and the microbiome in fibrotic lung diseases. This abstract is funded by: NHLBI, ATS, AHA