Smoking-dependent reprogramming of alveolar macrophage polarization

Implication for pathogenesis of chronic obstructive pulmonary disease

Renat Shaykhiev, Anja Krause, Jacqueline Salit, Yael Strulovici-Barel, Ben Gary Harvey, Timothy P. O'Connor, Ronald Crystal

Research output: Contribution to journalArticle

212 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2867-2883
Number of pages17
JournalJournal of Immunology
Volume183
Issue number4
DOIs
Publication statusPublished - 15 Aug 2009
Externally publishedYes

Fingerprint

Alveolar Macrophages
Chronic Obstructive Pulmonary Disease
Smoking
Genes
Phenotype
Chemokine CXCL9
Adenosine A3 Receptors
Macrophages
Chemokine CXCL10
Matrix Metalloproteinase 2
Bronchoalveolar Lavage
Principal Component Analysis
Transcriptome
Smoke
Tobacco Products
Real-Time Polymerase Chain Reaction
Pneumonia
Flow Cytometry
Inflammation
Gene Expression

ASJC Scopus subject areas

  • Immunology

Cite this

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.

In: Journal of Immunology, Vol. 183, No. 4, 15.08.2009, p. 2867-2883.

Research output: Contribution to journalArticle

Shaykhiev, Renat ; Krause, Anja ; Salit, Jacqueline ; Strulovici-Barel, Yael ; Harvey, Ben Gary ; O'Connor, Timothy P. ; Crystal, Ronald. / Smoking-dependent reprogramming of alveolar macrophage polarization : Implication for pathogenesis of chronic obstructive pulmonary disease. In: Journal of Immunology. 2009 ; Vol. 183, No. 4. pp. 2867-2883.
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