Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation

JCI Insight. 2017 Mar 23;2(6):e92465. doi: 10.1172/jci.insight.92465.


Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor-like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation.

Publication types

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

MeSH terms

  • Adrenomedullin / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Calcitonin Receptor-Like Protein / genetics*
  • Disease Progression
  • Female
  • Indomethacin / administration & dosage
  • Inflammation / pathology*
  • Intestinal Mucosa / pathology*
  • Lymphatic Vessels / metabolism*
  • Lymphatic Vessels / pathology
  • Male
  • Mice


  • Anti-Inflammatory Agents, Non-Steroidal
  • Calcitonin Receptor-Like Protein
  • Adrenomedullin
  • Indomethacin