RT Journal Article
SR Electronic
T1 LINGO3 interacts with Trefoil factor 2 to enforce mucosal barrier integrity and drive tissue repair during colitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 469684
DO 10.1101/469684
A1 Kelly M. Zullo
A1 Yingbiao Ji
A1 Yun Wei
A1 Karl Herbine
A1 Nicole Maloney
A1 Rachel Cohen
A1 Christopher Pastore
A1 Ma Samsouk
A1 Sriram Srivatsa
A1 Li Yin Hung
A1 Michael H. Kohanski
A1 Noam A. Cohen
A1 De’Broski R. Herbert
YR 2018
UL http://biorxiv.org/content/early/2018/11/13/469684.abstract
AB Mucosal epithelia are constantly exposed to damaging stimuli from mechanical, chemical, or biologic entities, and depend on rapid repair mechanisms to maintain tissue homeostasis and immunological quiescence. The reparative cytokine Trefoil factor 2 (TFF2) serves to enforce mucosal barrier integrity, but whether TFF2 receptor(s) exist is controversial. Herein, we demonstrate leucine rich repeat and immunoglobulin like domain containing nogo receptor interacting protein 3 (LINGO3) is a necessary transmembrane component for TFF2-mediated ERK signaling, proliferation, and recovery of trans-epithelial resistance of primary epithelia during wound healing. Human respiratory and intestinal epithelia express LINGO3 and mice lacking Lingo3 have impaired intestinal barrier function and fail to recover from DSS-induced colitis. Compared to wild-type controls, LINGO3 deficiency impairs both crypt regeneration and expression of the intestinal stem cell marker Lgr5. Importantly, Lingo3-/- mice display a phenotype similar to that previously reported for Tff2 deficiency, with increased paracellular permeability, and significant accumulation of mucosal CD4+ TH1 cells expressing IFNγ+ TNF+ even under steady-state conditions. Combined, these data reveal a previously unrecognized role for LINGO3 as a putative TFF2 receptor that regulates mucosal barrier integrity and GI inflammation.Significance Intestinal epithelial cells (IEC) are necessary for maintenance of homeostasis, resistance to infectious organisms, and overall organismal health. When injured the IEC and the underlying stroma and progenitor cell pool undergo restitutive and regenerative processes driven by the reparative cytokine Trefoil factor 2 (TFF2). This report identifies a novel receptor component for TFF2 signaling expressed on both human and mouse epithelial cells that is necessary for barrier integrity at the steady state and during colitic disease. The discovery of a novel TFF2-LINGO3 axis sheds new light on the processes controlling tissue repair, restitution, and regeneration at the mucosal interface.