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Updated: Jun 2, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse
Christopher J Harvey1, Rajesh K Thimmulappa, Sanjay Sethi
1Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA.
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.
Insights
Sulforaphane, a phytochemical, restores bacterial phagocytosis in COPD patients by activating Nrf2 signaling. This enhances immune defense and reduces inflammation, offering a potential strategy to prevent COPD exacerbations.
Area of Science:
- Immunology
- Pulmonology
- Molecular Biology
Background:
- Chronic obstructive pulmonary disease (COPD) is characterized by impaired innate immunity, specifically defective macrophage phagocytosis, leading to recurrent bacterial infections and exacerbations.
- Nuclear erythroid-related factor 2 (Nrf2) signaling is diminished in COPD, potentially compromising the lung's defense against oxidative stress and infection.
Purpose of the Study:
- To investigate whether sulforaphane, an Nrf2 activator, can restore phagocytic function in alveolar macrophages from COPD patients.
- To determine the role of Nrf2 and its downstream targets in mediating the protective effects of sulforaphane against bacterial infections in a COPD model.
Main Methods:
- Alveolar macrophages from COPD patients were treated with sulforaphane to assess phagocytosis of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA).
- Wild-type and Nrf2-deficient mice exposed to cigarette smoke were treated with sulforaphane to evaluate pulmonary bacterial clearance and inflammation.
- Gene expression and promoter analyses were performed to identify Nrf2-regulated genes involved in phagocytosis, focusing on the scavenger receptor MARCO.
Main Results:
- Sulforaphane treatment significantly restored bacteria recognition and phagocytosis by alveolar macrophages from COPD patients.
- In a mouse model of COPD, sulforaphane enhanced bacterial clearance and reduced inflammation, but these effects were abolished in Nrf2-deficient mice.
- Nrf2 directly up-regulates the scavenger receptor MARCO, which is crucial for sulforaphane-mediated enhancement of bacterial phagocytosis.
Conclusions:
- Activation of Nrf2 signaling by sulforaphane improves macrophage phagocytosis and bacterial clearance in COPD.
- The Nrf2-MARCO pathway is critical for enhancing antibacterial defenses in COPD macrophages.
- Targeting the Nrf2 pathway with agents like sulforaphane presents a promising therapeutic strategy for preventing bacterial exacerbations in COPD.
