Epigenetics and Cyclooxygenase-2 Mediate Dysfunction in Alveolar Macrophages and Polymorphonuclear Neutrophils Post-bone Marrow Transplantation.

Impaired lung innate immunity post-bone marrow transplantation;Microbiology and Immunology;Health Sciences;Immunology

Domingo-Gonzalez, RacquelO ; ; Riordan, Mary X. D. ;

University of Michigan

关键词: Impaired lung innate immunity post-bone marrow transplantation;    Microbiology and Immunology;    Health Sciences;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/110388/rdomingo_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Infectious pulmonary complications limit the success of hematopoietic stem cell transplant (HSCT) therapy in both autologous and allogeneic patients. Susceptibility to pathogens, like Pseudomonas aeruginosa and Staphylococcus aureus, persists despite successful immune reconstitution. Despite high incidence of infectious pulmonary complications following HSCT, relatively little is known about the mechanisms promoting enhanced susceptibility. Alveolar macrophages (AMs) are the sentinel phagocytes in the lung and following infection polymorphonuclear neutrophils (PMNs) assist in bacterial clearance. Previous human studies implicate AM and PMN impairment post-HSCT. Using a murine syngeneic or allogeneic bone marrow transplant (BMT) model, our studies explore the mechanisms involved in promoting HSCT AM and PMN defects. We show that syngeneic BMT mice display increased susceptibility to both P. aeruginosa and S. aureus, which correlated with impaired AM function. Altered class A scavenger receptors impaired AM uptake of P. aeruginosa but not S. aureus, while defective bacterial killing conferred overall susceptibility to these pathogens. Syngeneic BMT AM susceptibility is promoted by upregulation of prostaglandin E2 (PGE2) and its rate-limiting enzyme, cyclooxygenase-2 (COX)-2. Studies exploring the etiology of enhanced COX-2 expression revealed a loss in DNA methylation of the COX-2 promoter mediated by transforming growth factor (TGF)-ß-induced miRNA-29b, resulting in elevated COX-2. Previous data show COX-2/PGE2 impaired PMN bacterial killing but had no effect on phagocytosis post-syngeneic BMT. Here we show that upregulation of COX-2/ PGE2 inhibits PMN extracellular trap (NET) formation post-syngeneic and allogeneic BMT, a novel finding that identifies PGE2 as a physiologically relevant inhibitor of NETosis. Together, these findings highlight the importance of epigenetic changes (DNA methylation and miRNA) in BMT AMs, as they directly and indirectly result in increased COX-2 expression and PGE2 production. Upregulation of this pathway establishes an immunosuppressive environment in the lung through the inhibition of AM and PMN functions. Moreover, these findings identify potential therapeutic avenues to further explore in HSCT patients.