Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists

Bewley, Martin A.; Budd, Richard J.; Ryan, Elizabeth P.; Cole, Joby; Collini, Paul; Marshall, Jennifer L.; Kolsum, Umme; Beech, Gussie; Emes, Richard D.; Tcherniaeva, Irina; Berbers, Gguy A.M.; Walmsley, Sarah R.; Donaldson, Gavin C.; Wedzicha, Jadwiga A.; Kilty, Iain; Rumsey, William L.; Sánchez, Yolanda; Brightling, Christopher E.; Donnelly, Louise; Barnes, Peter J.; Singh, Dave; Whyte, Moira K. B.; Dockrell, David H.

doi:10.1164/rccm.201705-0903oc

Cited by 59 publications

(71 citation statements)

References 52 publications

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“…Interestingly, MDM from smokers without COPD did not respond to exogenous oxidative stress, which could indicate a protective mechanism within smoker cells, such as increased expression of anti-oxidants. This is important as we have already demonstrated the role of Nrf2 in COPD [37].…”

Section: Discussionmentioning

confidence: 78%

Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

et al. 2019

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Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD.Monocyte-derived macrophages (MDMs) were generated from non-smoker, smoker and COPD subjects, differentiated in either granulocyte macrophage-colony stimulating factor (G-Mφ) or macrophage-colony stimulating factor (M-Mφ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage fluid. Macrophages were incubated in ±200 µM H2O2 for 24 h, then exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, after which phagocytosis, mitochondrial ROS (mROS) and mitochondrial membrane potential (ΔΨm) were measured.Phagocytosis of bacteria was significantly decreased in both G-Mφ and M-Mφ from COPD patients compared with from non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or ΔΨm; however, in COPD, phagocytosis increased early mROS and decreased ΔΨm in both G-Mφ and M-Mφ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages and non-smoker MDMs, associated with reduced mROS production.COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

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Section: Discussionmentioning

confidence: 78%

Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

et al. 2019

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“…Pharmacological activation of NRF2 by sulforaphane, or a compound that disrupts the interaction of KEAP1 with NRF2, reversed the impaired bacterial phagocytosis by cultured alveolar macrophages and monocyte-derived macrophages isolated from patients with COPD 70,100 . However, daily oral administration of sulforaphane (extracted from broccoli sprouts) to COPD patients did not result in consistent changes in NRF2-dependent gene expression or markers of inflammation in alveolar macrophages and bronchial epithelial cells at the doses used 101 , illustrating some of the challenges in translating findings from cell culture studies to humans.…”

Section: Respiratory Diseasementioning

confidence: 99%

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Cuadrado

Rojo

Wells

et al. 2019

Nat Rev Drug Discov

951

950

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Transcription factor NF-E2 p45-related factor 2 (NRF2, gene name NFE2L2) and its principal negative regulator, the E3 ligase adapter Kelch-like ECH-associated protein 1 (KEAP1), play a critical role in the development and progression of chronic diseases of the lung and liver, autoimmune, neurodegenerative and metabolic disorders, and also cancer. NRF2 activation provides cytoprotection against numerous pathologies characterized by chronic inflammation, metabolic alterations and redox disturbances. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy, and safety remain.

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“…The cells were then incubated with benzyl-penicillin and gentamicin to kill remaining extracellular bacteria, as described. The cells were lysed in saponin and live intracellular bacteria quantified by the Miles Misra method (37).…”

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confidence: 99%

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Kitchen

Cunningham

Poolman

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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103

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The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1−/− macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1−/− macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.

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Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists

Abstract: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.

Cited by 59 publications

References 52 publications

Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

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