Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure

Our plain-English summary of Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure, by S. Murthy, J.L. Larson-Casey, A.J. Ryan, et al (FASEB Journal, 2015).

The study

• Authors: S. Murthy, J.L. Larson-Casey, A.J. Ryan, C. He, L. Kobzik, A.B. Carter
• Journal: FASEB Journal
• Published: 2015;29(8):3527-36
• Cited by: 110 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Alternative activation of alveolar macrophages is linked to fibrosis following exposure to asbestos. The scavenger receptor, macrophage receptor with collagenous structure (MARCO), provides innate immune defense against inhaled particles and pathogens; however, a receptor for asbestos has not been identified. We hypothesized that MARCO acts as an initial signaling receptor for asbestos, polarizes macrophages to a profibrotic M2 phenotype, and is required for the development of asbestos-induced fibrosis. Compared with normal subjects, alveolar macrophages isolated from patients with asbestosis express higher amounts of MARCO and have greater profibrotic polarization. Arginase 1 (40-fold) and IL-10 (265-fold) were higher in patients. In vivo, the genetic deletion of MARCO attenuated the profibrotic environment and pulmonary fibrosis in mice exposed to chrysotile. Moreover, alveolar macrophages from MARCO(-/-) mice polarize to an M1 phenotype, whereas wild-type mice have higher Ym1 (>3.0-fold) and nearly 7-fold more active TGF-β1 in bronchoalveolar lavage (BAL) fluid (BALF). Arg(432) and Arg(434) in domain V of MARCO are required for the polarization of macrophages to a profibrotic phenotype as mutation of these residues reduced FIZZ1 expression (17-fold) compared with cells expressing MARCO. These observations demonstrate that a macrophage membrane protein regulates the fibrotic response to lung injury and suggest a novel target for therapeutic intervention.

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In plain English

This laboratory study tested whether the macrophage scavenger receptor MARCO acts as a receptor for chrysotile asbestos and drives profibrotic (M2) macrophage polarization. The authors compared alveolar macrophages recovered by bronchoalveolar lavage from normal volunteers and patients with asbestosis, exposed wild-type and MARCO-deficient mice intratracheally to titanium dioxide or chrysotile, and carried out cell-culture experiments with macrophage cell lines. Macrophages from patients with asbestosis expressed significantly more MARCO, produced hydrogen peroxide at a higher rate, and showed greater than 40-fold higher arginase 1 and 265-fold higher IL-10 expression than those from normal subjects. In mice, chrysotile induced MARCO expression; MARCO-deficient mice exposed to chrysotile had essentially normal lung histology, significantly less hydroxyproline and lower Ym1, while wild-type mice had nearly 7-fold more active TGF-beta1 in lavage fluid. Silencing MARCO reduced mitochondrial hydrogen peroxide and chrysotile binding, and mutating Arg432 and Arg434 reduced FIZZ-1 expression and arginase activity. The authors concluded that MARCO is required, at least in part, for chrysotile-induced pulmonary fibrosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental laboratory study combining human bronchoalveolar lavage samples, knockout-mouse in vivo exposures, and in vitro macrophage cell culture
• Who was studied: Alveolar macrophages from normal volunteers (n = 8) and patients with asbestosis (n = 9) at the University of Iowa; wild-type C57Bl/6 and MARCO-deficient mice; human THP-1 monocyte and mouse MH-S alveolar macrophage cell lines
• Exposure: Chrysotile asbestos, with titanium dioxide (TiO2) as an inert control particle, given intratracheally at 100 micrograms per mouse
• Main results:
  • Alveolar macrophages from patients with asbestosis expressed significantly more MARCO than those from normal subjects
  • In patients with asbestosis, arginase 1 was more than 40-fold and IL-10 265-fold higher than in normal subjects
  • Patients' alveolar macrophages produced hydrogen peroxide at a significantly higher rate than normal subjects' cells
  • Chrysotile-exposed MARCO-deficient mice had essentially normal lungs, whereas chrysotile-exposed wild-type mice had dense collagen deposition
  • Lungs of chrysotile-exposed MARCO-deficient mice contained significantly less hydroxyproline than those of wild-type mice
  • Wild-type mice had higher Ym1 (greater than 3.0-fold) in lavage fluid than MARCO-deficient mice
  • Active TGF-beta1 in wild-type mice was nearly 7-fold higher than in chrysotile-exposed MARCO-deficient mice
  • MARCO-deficient mice had significantly higher M1 markers TNF-alpha and IL-1beta, which did not change with chrysotile exposure
  • In macrophages with MARCO knocked down, chrysotile binding was less than half that of cells with scrambled siRNA
  • Mutating Arg432 or Arg434 attenuated, and mutating both abolished, chrysotile-induced H2O2 production
  • MARCO was undetectable in alveolar macrophages of unexposed mice but present at all times after chrysotile exposure (3, 7, 14, 21 days)
• The authors' conclusion: The authors concluded that MARCO is required, at least in part, for pulmonary fibrosis following exposure to chrysotile, and suggested MARCO as a potential therapeutic target
• Limitations the authors state:
  • The authors noted that no interacting partners for MARCO have been identified, leaving the proposed downstream signalling mechanism unresolved

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile.

Medical terms in this study, explained in our Lexicon: Macrophage, Pulmonary Fibrosis, Alveolar Macrophage, Fibrosis, Chrysotile, Bronchoalveolar Lavage (BAL).

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