Abstract
Resistin-like molecule alpha (RELMα) and YM-1 are secreted proteins implicated in murine models of alternatively activated macrophage (AA/M2) accumulation and Th2-skewed inflammation. Since the gp130 cytokine Oncostatin M (OSM) induces a Th2-like cytokine and AA/M2 skewed inflammation in mouse lung, we here investigated regulation of RELMα and YM-1. Transient pulmonary overexpression of OSM by Adenovirus vector (AdOSM) markedly induced RELMα and YM-1 protein expression in total lung. In situ hybridization showed that RELMα mRNA was highly induced in airway epithelial cells (AEC) and was co-expressed with CD68 mRNA in some but not all CD68+ cells in parenchyma. IL-6 overexpression (a comparator gp130 cytokine) induced RELMα, but at significantly lower levels. IL-6 (assessing IL-6−/− mice) was not required, nor was STAT6 (IL-4/13 canonical signalling) for AdOSM-induction of RELMα in AEC. AEC responded directly to OSM in vitro as assessed by pSTAT3 activation. RELMα-deficient mice showed similar inflammatory cell infiltration and cytokine responses to wt in response to AdOSM, but showed less accumulation of CD206+ AA/M2 macrophages, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, and TIMP1, and reduced parenchymal alpha smooth muscle actin. Thus, RELMα is regulated by OSM in AEC and contributes to extracellular matrix remodelling in mouse lung.
Highlights
Chronic respiratory diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and severe asthma, are conditions that imply a reduction in lung function that involves extracellular matrix (ECM) remodelling [1]
We show here that Oncostatin M (OSM) is a potent inducer of RELMα in airway epithelial cells, markedly increases RELMα levels locally in lung, and that RELMα contributes to the ECM
Lung tissues were assessed for RELMα mRNA expression, and broncho-alveolar lavage (BAL) fluid and serum were analyzed for RELMα protein
Summary
Chronic respiratory diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and severe asthma, are conditions that imply a reduction in lung function that involves extracellular matrix (ECM) remodelling [1]. In COPD, damaged alveolar walls and the loss of shape and structure in larger airways reduce gas exchange efficiency [2], whereas IPF and severe asthma are characterized by excessive ECM deposition in the airways or around alveoli, decreasing gas exchange with the capillary network and impairing pulmonary function [1,3,4]. These conditions are often progressive in nature and current therapies have much room for improvement [3,5]. Understanding the various mechanisms of how ECM remodelling occurs and through which cells and signaling molecules will provide a better understanding to inform new potential therapeutic approaches separate from the TGFβ pathway
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