Th17/Treg imbalance in COPD progression: A temporal analysis using a CS-induced model

PLoS One. 2019 Jan 10;14(1):e0209351. doi: 10.1371/journal.pone.0209351. eCollection 2019.

Abstract

Background: The imbalance between pro- and anti-inflammatory immune responses plays a pivotal role in chronic obstructive pulmonary disease (COPD) development and progression. To clarify the pathophysiological mechanisms of this disease, we performed a temporal analysis of immune response-mediated inflammatory progression in a cigarette smoke (CS)-induced mouse model with a focus on the balance between Th17 and Treg responses.

Methods: C57BL/6 mice were exposed to CS for 1, 3 or 6 months to induce COPD, and the control groups were maintained under filtered air conditions for the same time intervals. We then performed functional (respiratory mechanics) and structural (alveolar enlargement) analyses. We also quantified the NF-κB, TNF-α, CD4, CD8, CD20, IL-17, IL-6, FOXP3, IL-10, or TGF-β positive cells in peribronchovascular areas and assessed FOXP3 and IL-10 expression through double-label immunofluorescence. Additionally, we evaluated the gene expression of NF-κB and TNF in bronchiolar epithelial cells.

Results: Our CS-induced COPD model exhibited an increased proinflammatory immune response (increased expression of the NF-κB, TNF-α, CD4, CD8, CD20, IL-17, and IL-6 markers) with a concomitantly decreased anti-inflammatory immune response (FOXP3, IL-10, and TGF-β markers) compared with the control mice. These changes in the immune responses were associated with increased alveolar enlargement and impaired lung function starting on the first month and third month of CS exposure, respectively, compared with the control mice.

Conclusion: Our results showed that the microenvironmental stimuli produced by the release of cytokines during COPD progression lead to a Th17/Treg imbalance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cellular Microenvironment / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Inflammation Mediators / metabolism
  • Lung / pathology
  • Lung / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Disease, Chronic Obstructive / etiology
  • Pulmonary Disease, Chronic Obstructive / immunology*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Respiratory Mechanics
  • Smoking / adverse effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Time Factors

Substances

  • Biomarkers
  • Cytokines
  • Inflammation Mediators

Grants and funding

The Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant 2014/15819–8 - FDTQSL) played a role in the data collection and analysis, and in preparation of the manuscript. The Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (demanda social - JTI) provided the scholarship to the first author who played a role in the study design, data collection and analysis, and preparation of the manuscript. The Instituto dos Laboratórios de Investigação Médica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - LIM-20 played a role in the data collection. The Fundação Faculdade de Medicina through the Programa de Fomento às Atividades de Pesquisa supported in the payment of English language review expenses and publication costs.