Abstract
Chronic Obstructive Pulmonary Disease (COPD) stands as a notorious contender among the leading causes of death globally, with current therapies only offering symptomatic relief without a definitive cure. In a significant stride towards understanding the molecular basis of COPD, a recent study uncovers the role of the non-canonical Notch ligand, DNER, in regulating macrophage function and its impact on disease severity and progression. This article delves into the findings from EBioMedicine that may pave the way for novel therapeutic avenues.
Introduction
Chronic Obstructive Pulmonary Disease affects millions worldwide, being the third leading cause of death (Burney et al., 2015). COPD is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities, commonly attributed to significant exposure to harmful particulates or gases. The pathogenesis of COPD is complex, involving airway inflammation, emphysema, and mucus hypersecretion (Barnes, 2017).
Recent research published in EBioMedicine by Ballester-López et al. (2019) shows promising insights into the molecular pathology of COPD. The study identified the Notch ligand delta/notch-like epidermal growth factor-related receptor (DNER) as an influencer of macrophage IFNγ release in COPD, shedding light on a hitherto overlooked aspect of COPD immunity (DOI: 10.1016/j.ebiom.2019.03.054).
Current Understanding of COPD Pathology
Cigarette smoke (CS) is the primary risk factor for COPD. It induces local inflammation in the lung with macrophage activation playing a central role (Barnes, 2008). However, the detailed mechanisms leading from macrophage activation to tissue damage in COPD have remained elusive. With the increase in incidence of the disease, a detailed understanding of these mechanisms is imperative to develop targeted therapies.
DNER and Its Implications in COPD
The study by Ballester-López and colleagues takes a closer look at the role of DNER in COPD. Through microarray analysis and immunofluorescence staining, it was observed that DNER localizes to macrophages in lung tissue from COPD patients and mice exposed to CS. Moreover, the expression of DNER was found to be regulated in response to inflammation.
Specifically, macrophages deficient in DNER exhibited impaired signaling through NICD1 (Notch intracellular domain 1)/NFKB (nuclear factor kappa-light-chain-enhancer of activated B cells), which are critical for IFNγ production—a key player in inflammation and immune response.
The study further demonstrated that DNER deficient mice exposed to CS had reduced IFNγ production and Notch1 activation in recruited macrophages. This protected against emphysema and lung dysfunction, indicating a potential protective role against COPD progression.
Implications for Future Therapies
The research carries significant therapeutic potential. By targeting DNER, it may be possible to modulate macrophage function and inflammation, offering a new approach in COPD treatment. The findings suggest that DNER could be a novel biomarker for disease severity and a target for pharmaceutical intervention.
Conclusion
The identification of DNER as a regulator of macrophage IFNγ release provides valuable insights into the immunopathology of COPD. The protective effect observed in DNER deficient mice against CS-induced lung damage and dysfunction indicates the potential for therapeutic manipulation of this pathway. This knowledge opens promising avenues for future research and therapy development, which is paramount for a disease currently lacking a cure.
Keywords
1. Chronic Obstructive Pulmonary Disease (COPD)
2. Immune response in COPD
3. DNER protein role in COPD
4. Macrophage regulation in lung disease
5. Novel COPD therapeutic targets
References
Ballester-López, C., Conlon, T.M., Ertüz, Z., Greiffo, F.R., Irmler, M., Verleden, S.E., … Yildirim, A.Ö. (2019). The Notch ligand DNER regulates macrophage IFNγ release in chronic obstructive pulmonary disease. EBioMedicine, 43, 562-575. DOI: 10.1016/j.ebiom.2019.03.054
Burney, P.G., Patel, J., Newson, R., Minelli, C., & Naghavi, M. (2015). Global and regional trends in COPD mortality, 1990-2010. Eur Respir J, 45(5), 1239-1247. DOI: 10.1183/09031936.00142414
Barnes, P.J. (2017). Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond), 131(13), 1541-1558. DOI: 10.1042/CS20160350
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