title: Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model.
abstract: Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid-related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. Here, we test whether activation of Nrf2 by the phytochemical sulforaphane restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Sulforaphane treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients. Furthermore, sulforaphane treatment enhanced pulmonary bacterial clearance by alveolar macrophages and reduced inflammation in wild-type mice but not in Nrf2-deficient mice exposed to cigarette smoke for 6 months. Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Harvey
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Thimmulappa
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
authors.forename: Xiaoni
authors.initials: X
authors.lastname: Kong
authors.forename: Lonny
authors.initials: L
authors.lastname: Yarmus
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Feller-Kopman
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006193:Haemophilus influenzae / Q000472:pathogenicity; D006801:Humans; D017879:Isothiocyanates; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D011971:Receptors, Immunologic / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000627:therapeutic use
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D011971:Receptors, Immunologic; D013454:Sulfoxides; D013861:Thiocyanates; C016766:sulforaphane