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

LR Young, PM Gulleman, CW Short, H Tanjore… - JCI insight, 2016 - ncbi.nlm.nih.gov
LR Young, PM Gulleman, CW Short, H Tanjore, T Sherrill, A Qi, AP McBride…
JCI insight, 2016ncbi.nlm.nih.gov
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 …
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.
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