Project ID CM-HD2024_07

ThemeCM-HD

Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Additional Supervisor Prof Mona Bafadhel

Impact of particulate matter air pollution on neutrophil function in healthy and asthmatic patients.

SCIENTIFIC BASIS:
Severe asthma and Chronic Obstructive Pulmonary Disease (COPD) are characterised by neutrophil-dominated lung inflammation. Neutrophils, the most abundant circulating white blood cells, are equipped with a plethora of antimicrobial weapons such as phagocytosis, degranulation of antimicrobial compounds, production of Reactive Oxygen Species (ROS) and Neutrophil Extracellular Traps (NETs). Particulate matter air pollution (PM) poses a huge burden on health. Patients with chronic airway conditions are particularly vulnerable. PM induces excessive neutrophilic inflammation and consequently tissue damage and pathology. The goal of this project is to develop strategies that can mitigate the detrimental effects of air pollution and improve lung health by limiting neutrophilic inflammation while preserving immune defense mechanisms.

AIMS:
1) Investigate how real-world PM from different sources globally (e.g. urban or forest burning locations) impact the functions of neutrophils.
2) Identify molecular signalling pathways that directly or indirectly influence neutrophil function.
3) Compare PM-induced activation of neutrophils from healthy donors and patients with chronic airway disease and identify strategies to ameliorate excess inflammatory responses.

EXPERIMENTAL APPROACH:
Techniques will include cell isolation and culture, flow cytometry, protein and gene expression analyses and advanced microscopy. Neutrophils will be isolated from blood samples, airway epithelial cultures will be grown at air-liquid interface (ALI), and co-culture systems involving different immune cells will be utilized.

OBJECTIVES:
Year 1: Establish essential methodologies including the isolation of donor neutrophils, inducing ALI cultures, and characterizing the heterogeneity of real-world PM samples.
Year 2: Understand the impact of PM on neutrophil functions directly and in co-culture systems with relevant airway cells.
Year 3: Determine the molecular pathways through which PM affects neutrophil function.
Year 4: Comparing responses to PM between neutrophils from healthy individuals versus asthma and COPD patients we aim to identify public health interventions that can mitigate against detrimental effects.

Representative Publications

Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. 2015 Jul 17, In: Science. 349(6245):316-20. doi: 10.1126/science.aaa8064. Epub 2015 Jul 16. PMID: 26185250; PMCID: PMC4854322. Reactive Oxygen Species Localization Programs Inflammation to Clear Microbes of Different Size. Warnatsch A, Tsourouktsoglou TD, Branzk N, Wang Q, Reincke S, Herbst S, Gutierrez M, Papayannopoulos V. 2017 Mar 21, In: Immunity. 46(3):421-432. doi: 10.1016/j.immuni.2017.02.013. Epub 2017 Mar 14. PMID: 28314592; PMCID: PMC5965455. Histones, DNA, and Citrullination Promote Neutrophil Extracellular Trap Inflammation by Regulating the Localization and Activation of TLR4. Tsourouktsoglou TD, Warnatsch A, Ioannou M, Hoving D, Wang Q, Papayannopoulos V. 2020 May 5, In: Cell Reports. 31(5):107602. doi: 10.1016/j.celrep.2020.107602. PMID: 32375035.
Air pollution and its effects on the immune system. Glencross, D. A., Ho, T. R., Camiña, N., Hawrylowicz, C. M. & Pfeffer, P. E., 1 May 2020, In: Free Radical Biology and Medicine. 151, p. 56-68. https://doi.org/10.1016/j.freeradbiomed.2020.01.179 Effects of vitamin D on inflammatory and oxidative stress responses of human bronchial epithelial cells exposed to particulate matter. Pfeffer, P. E., Lu, H., Mann, E. H., Chen, Y-H., Ho, T-R., Cousins, D. J., Corrigan, C. J., Kelly, F. J., Mudway, I. S. & Hawrylowicz, C. M., 29 Aug 2018, In: PLOS One. https://doi.org/10.1371/journal.pone.0200040 Vitamin D counteracts an IL-23-dependent IL-17A+IFN-γ+ response driven by urban particulate matter. Mann, E. H., Ho, T-R., Pfeffer, P. E., Matthews, N. C., Chevretton, E., Mudway, I. S., Kelly, F. J. & Hawrylowicz, C. M., 30 Sep 2017, In: American Journal of Respiratory Cell and Molecular Biology. 57, 3, p. 355-366. https://doi.org/10.1165/rcmb.2016-0409OC