@article{3bfd4dde435a47d79c8169bde9e6ff67,
title = "Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor",
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.",
keywords = "Crohn's disease, cytokine signaling, endothelium, inflammation, inflammatory bowel disease, lympho-organogenesis, lymphocyte migration",
author = "Czepielewski, {Rafael S.} and Erlich, {Emma C.} and Onufer, {Emily J.} and Shannon Young and Saunders, {Brian T.} and Han, {Yong Hyun} and Mary Wohltmann and Wang, {Peter L.} and Kim, {Ki Wook} and Shashi Kumar and Hsieh, {Chyi Song} and Scallan, {Joshua P.} and Ying Yang and Zinselmeyer, {Bernd H.} and Davis, {Michael J.} and Randolph, {Gwendalyn J.}",
note = "Funding Information: This work was funded by NIH grant DP1 DK1109668 and a Synergy Grant from the Rainin Foundation to G.J.R. and M.J.D. Additional support included NIH grants R01 HL145397 to Y.Y., R01 HL142905 to J.P.S., and R37 AI0499653 to G.J.R., with the latter including a Primary Caregiver Supplement to support career development of E.J.O. E.J.O. also received support from T32 DK077653 . R.S.C. was supported by a fellowship award “ FA-2020-01-IBD-1 from the Lawrence C. Pakula, MD IBD Education & Innovation Fund ”. Histology was carried out using core facilities supported by the Digestive Diseases Research Core Center of Washington University, funded by NIH P30 DK052574 . We thank Natalia Jaeger for experimental support. TNF ΔARE mice were obtained from the Cleveland DDRCC, supported by NIH P30 DK097948 , and we thank Dr. T. Pizarro and F. Cominelli for facilitating access to the strain through the Cleveland DDRCC. Requests for this strain should be directed to the Cleveland DDRCC via MTA. Graphical abstract created with BioRender.com . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = dec,
day = "14",
doi = "10.1016/j.immuni.2021.10.003",
language = "English",
volume = "54",
pages = "2795--2811.e9",
journal = "Immunity",
issn = "1074-7613",
number = "12",
}