Myeloid-Specific Fos-Related Antigen-1 Regulates Cigarette Smoke–Induced Lung Inflammation, Not Emphysema, in Mice

Abstract

Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.Keywords: emphysema; inflammation; activator protein-1; lung; macrophages Clinical RelevancePersistent macrophagic inflammation in the smoker's lung has been implicated in the development and perpetuation of chronic obstructive pulmonary disease (COPD). Here, we demonstrate, using a tissue-specific knockout model, that Fosrelated antigen-1 (Fra-1) transcription factor signaling in myeloid cells plays a key role in promoting chronic cigarette smoke-induced lung macrophagic inflammation in vivo. Thus, either depletion or inhibition of Fra-1 activity may be useful in dampening lung inflammation in patients with COPD.Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide. The disease is characterized by chronic inflammation of peripheral and central airways, increased thickness of airway walls, and destruction of alveolar septa, ultimately leading to the destruction of the alveolar walls (1). Although cigarette smoking is a major risk factor for COPD, the exact mechanism(s) underlying cigarette smoke (CS)-induced lung inflammation and emphysema is not yet fully understood and Author Contributions: M.V. and S.P.R. were involved in the conception, delineation of hypotheses, and design of the study, as well as the analysis and interpretation of data; M.V. performed in v...

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