Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome

JCI Insight. 2016 Oct 20;1(17):e88947. doi: 10.1172/jci.insight.88947.

Abstract

Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bleomycin
  • Chemokine CCL2 / metabolism
  • Disease Susceptibility
  • Epithelial Cells / cytology*
  • Female
  • Hermanski-Pudlak Syndrome / immunology*
  • Macrophages / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Serine-Threonine Kinases / metabolism
  • Pulmonary Alveoli / cytology
  • Pulmonary Fibrosis / immunology*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, CCR2 / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Receptors, CCR2
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Bleomycin
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II