Abstract
Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease often leading to patient death [1,2,3]
There was a significant increase in CCL18 protein production by collagen type I stimulated alveolar macrophages (AM) from healthy donors compared to non stimulated control (p
The effect was more pronounced in AM from patients with IPF (CCL2: p
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease often leading to patient death [1,2,3]. Increased collagen type I production and accumulation is the hallmark of IPF [1,4]. Collagens build the scaffold of the human body and are the major constituent of extracellular matrix (ECM) [4]. The balance between collagen degradation and production is tightly regulated in normal tissues. Compelling evidence indicates that collagen degrading enzymes and collagen turnover are increased in IPF, the end result is abundant collagen type I deposition [5,6,7]. In the process of degradation, firstly the crosslinks have to be cleaved resulting in collagen type I monomers. Triple helical collagen type I monomers contain multiple cleavage sites for metalloproteinases (MMP) as well as multiple binding sites for cells, cytokines, and other extracellular matrix proteins [6,8]. The distinct immune response following stimulation of alveolar macrophages (AM) by collagen type I monomers and its underlying mechanisms have, to our knowledge, far, not been addressed
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