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-typemice but not in Nrf2-deficientmice 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.

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

“…Antioxidative and antimicrobial properties of SFN, like the induction of phase II detoxifying enzymes and the inhibition of H. pylori growth, seem to contribute to its anticarcinogenic properties (6). More recent reports unraveled beneficial effects of SFN in experimental chronic obstructive pulmonary disease (COPD) (28,53). SFN reduced pulmonary inflammation in COPD, a condition associated with Th17 responses (54,55).…”

“…Yet, the exact effects of SFN on immune responses have been mainly studied in the setting of cancer or microbial infections. SFN enhances bacterial clearance by increasing the phagocytic activity of alveolar macrophages (28) and is beneficial against Helicobacter pylori infections (13). In contrast, high doses of SFN seem to decrease the expression of innate cytokines like IL-6, TNF, and IL-1 by macrophages in vitro in response to LPS (29).…”

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

“…Bacterial phagocytosis was analyzed by flow cytometry as described previously (20). For analyzing bactericidal activity, macrophages were incubated with P. aeruginosa for 4 hours and bacterial growth was assessed in cell-free culture medium as described previously (20).…”

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

“…Autophagic death of smoke-exposed airway epithelial cells is suspected to play a pathogenic role in COPD; Nrf2 opposes this, at least in part by inducing p62, which in turn blocks overexpression of the autophagy mediator LC3B [60]. By inducing the scavenger receptor MARCO, Nrf2 enhances the capacity of alveolar macrophages to phagocytize bacterial pathogens that episodically exacerbate the clinical course of COPD patients [61]. Via its antioxidant effects, Nrf2 helps to preserve the expression and activity of the deacetylase HDAC2; [62,63].…”