title: PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment.
abstract: Defective IL-10 allele is a risk factor for intestinal inflammation. Indeed, IL-10(-/-) mice are predisposed to spontaneous colitis in the presence of intestinal microbiota, indicating that microbial factors contribute to developing intestinal inflammation. By recognizing flagellin, TLR5 plays a quintessential role in microbial recognition in intestinal epithelial cells. Here, we treated flagellin (1.0 μg/mouse/d) in mouse colon and found that it elicited colonic inflammation in IL-10(-/-) mice, characterized with tissue hypertrophy, inflamed epithelium, and enhanced cytokine production in the colon (MPO, KC, IL-6; ≥2-fold; P < 0.05). These inflammatory effects were dramatically inhibited in TLR5(-/-);IL-10(-/-) mice. Intestinal epithelium specific PTEN deletion significantly attenuated flagellin-promoted colonic inflammation in IL-10(-/-) mice. As a molecular mechanism that PTEN deletion inhibited TLR5-elicited responses, we hypothesized that PTEN regulated TLR5-induced responses by controlling the involvement of Mal in TLR5 engagement. Mal interacted with TLR5 on flagellin, and Mal deficiency inhibited flagellin-induced responses in intestinal epithelial cells. Similarly, Mal(-/-);IL-10(-/-) mice showed reduced flagellin-promoted responses. Furthermore, PTEN deletion disrupted Mal-TLR5 interaction, resulting in diminished TLR5-induced responses. PTEN deletion impeded Mal localization at the plasma membrane and suppressed Mal-TLR5 interaction. These results suggest that, by controlling Mal recruitment, PTEN regulates TLR5-induced inflammatory responses.
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Choi
authors.forename: Jane
authors.initials: J
authors.lastname: Jung
authors.forename: Hyo Kyun
authors.initials: HK
authors.lastname: Chung
authors.forename: Eunok
authors.initials: E
authors.lastname: Im
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Rhee
mesh_terms: D000818:Animals; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D051198:Toll-Like Receptor 5; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse