Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor

Rafael S. Czepielewski, Emma C. Erlich, Emily J. Onufer, Shannon Young, Brian T. Saunders, Yong Hyun Han, Mary Wohltmann, Peter L. Wang, Ki Wook Kim, Shashi Kumar, Chyi Song Hsieh, Joshua P. Scallan, Ying Yang, Bernd H. Zinselmeyer, Michael J. Davis, Gwendalyn J. Randolph

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.

Original languageEnglish
Pages (from-to)2795-2811.e9
JournalImmunity
Volume54
Issue number12
DOIs
StatePublished - Dec 14 2021

Keywords

  • Crohn's disease
  • cytokine signaling
  • endothelium
  • inflammation
  • inflammatory bowel disease
  • lympho-organogenesis
  • lymphocyte migration

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