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Smoking-Dependent Reprogramming of Alveolar Macrophage Polarization: Implication for Pathogenesis of Chronic Obstructive Pulmonary Disease

Shaykhiev, Renat, Krause, Anja, Salit, Jacqueline, Strulovici-Barel, Yael, Harvey, Ben-Gary, O'Connor, Timothy P, Crystal, Ronald G·2009·The Journal of Immunology
DOI 10.4049/jimmunol.0900473PMC PMC2873685
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Abstract

When exposed to a specific microenvironment, macrophages acquire either M1- or M2-polarized phenotypes associated with inflammation and tissue remodeling, respectively. Alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for chronic obstructive pulmonary disease (COPD), a disease characterized by lung inflammation and remodeling. Transcriptional profiling of AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers, and 12 COPD smokers was performed to test the hypothesis whether smoking alters AM polarization, resulting in a disease-relevant activation phenotype. The analysis revealed that AM of healthy smokers exhibited a unique polarization pattern characterized by substantial suppression of M1-related inflammatory/immune genes and induction of genes associated with various M2-polarization programs relevant to tissue remodeling and immunoregulation. Such reciprocal changes progressed with the development of COPD, with M1-related gene expression being most dramatically down-regulated (p < 0.0001 vs healthy nonsmokers, p < 0.002 vs healthy smokers). Results were confirmed with TaqMan real-time PCR and flow cytometry. Among progressively down-regulated M1-related genes were those encoding type I chemokines CXCL9, CXCL10, CXCL11, and CCL5. Progressive activation of M2-related program was characterized by induction of tissue remodeling and immunoregulatory genes such as matrix metalloproteinase (MMP)2, MMP7, and adenosine A3 receptor (ADORA3). Principal component analysis revealed that differential expression of polarization-related genes has substantial contribution to global AM phenotypes associated with smoking and COPD. In summary, the data provide transcriptome-based evidence that AM likely contribute to COPD pathogenesis in a noninflammatory manner due to their smoking-induced reprogramming toward M1-deactivated, partially M2-polarized macrophages.

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Metadata

Authors
Shaykhiev, R., Krause, A., Salit, J., Strulovici-Barel, Y., Harvey, B.-G., O'Connor, T. P., & Crystal, R. G.
Affiliations
Department of Genetic Medicine
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2009-08
Volume
183
Issue
4
Pages
2867-2883
ISSN
  • 1550-6606
  • 0022-1767
DOI
10.4049/jimmunol.0900473
PMC
PMC2873685
Cited by
359
References
7
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)

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