Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD)

Mathew Suji Eapen,Philip M Hansbro,Chris Ward,Richard Y Kim,Tillie-Louise Hackett,Kielan Mcalinden,Eugene H Walters,Sukhwinder Singh Sohal

doi:10.1038/s41598-017-13888-x

Abstract

We explore potential dysregulation of macrophage phenotypes in COPD pathogenesis through integrated study of human small airway tissue, bronchoalveolar lavage (BAL) and an experimental murine model of COPD. We evaluated human airway tissue and BAL from healthy controls, normal lung function smokers (NLFS), and COPD subjects. Both small airways and BAL cells were immunohistochemically stained with anti-CD68 for total macrophages and with anti-CD163 for M2, and anti-iNOS for M1 macrophages. Multiplex ELISA measured BAL cytokines. Comparable cigarette smoke-induced experimental COPD mouse model was assessed for relevant mRNA profiles. We found an increase in pro-inflammatory M1s in the small airways of NLFS and COPD compared to controls with a reciprocal decrease in M2 macrophages, which remained unchanged among pathological groups. However, luminal macrophages showed a dominant M2 phenotype in both NLFS and COPD subjects. BAL cytokine skewed towards an M2 profile with increase in CCL22, IL-4, IL-13, and IL-10 in both NLFS and COPDs. The mouse-model of COPD showed similar increase in mRNA for M2 markers. Our finding suggests abnormal macrophage switching in both mucosal and luminal areas of COPD patients, that strongly associated with cytokine balance. There may be potential for beneficial therapeutic cytokine manipulation of macrophage phenotypes in COPD.

Highlights

Airflow limitation is the defining feature of COPD and is due primarily to small airway wall fibrosis, thickening, and luminal narrowing and progressive obliteration
There was a significant increase in percent M1 population in normal lung function smokers (NLFS) [median percenatge18%; range 0–100; (p < 0.05)] and COPD current smoker (COPD-CS) [median percentage 21.2% range 0.0–64.1; (p < 0.01)], which reverted partially towards normal in COPD ex-smokers (COPD-ES) [median percentage 10% range 0.0–42; (p < 0.05)] (Fig. 1c)
No statistical significant difference was observed between NLFS and COPD-CS

Summary

Introduction

Airflow limitation is the defining feature of COPD and is due primarily to small airway wall fibrosis, thickening, and luminal narrowing and progressive obliteration. These events occur early in disease even before symptoms appear or lung function changes[1]. M2 macrophages are considered anti-inflammatory and are linked to tissue repair and fibrosis, secreting pro-Th2 cytokines including CCL22, IL-4, IL-13 and IL-10 14. The competition between iNOS and Arg-1 for L-arginine can drive contrasting pathologies functionally through opposed macrophage phenotypes[17]

Methods

Results

Discussion

Conclusion