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TLR Sorting by Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis

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TLR Sorting by Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis University of Massachusetts Medical School eScholarship@UMMS UMass Center for Clinical and Translational University of Massachusetts Center for Clinical Science Supported Publications and Translational Science 2014-09-01 TLR sorting by Rab11 endosomes maintains intestinal epithelial- microbial homeostasis Shiyan Yu Rutgers University Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/umccts_pubs Part of the Cell Biology Commons, Cells Commons, Cellular and Molecular Physiology Commons, Digestive System Commons, Genetic Phenomena Commons, Hemic and Immune Systems Commons, and the Translational Medical Research Commons Repository Citation Yu S, Nie Y, Ip YT, Gao N. (2014). TLR sorting by Rab11 endosomes maintains intestinal epithelial- microbial homeostasis. UMass Center for Clinical and Translational Science Supported Publications. https://doi.org/10.15252/embj.201487888. Retrieved from https://escholarship.umassmed.edu/ umccts_pubs/187 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in UMass Center for Clinical and Translational Science Supported Publications by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Published online: July 24, 2014 Article TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis Shiyan Yu1, Yingchao Nie2, Byron Knowles3, Ryotaro Sakamori1, Ewa Stypulkowski1, Chirag Patel4, Soumyashree Das1, Veronique Douard4, Ronaldo P Ferraris4, Edward M Bonder1, James R Goldenring3, Yicktung Tony Ip2 & Nan Gao1,5,* Abstract immune surveillance against luminal pathogenic stimuli (Artis, 2008; Maynard et al, 2012). Mature human IECs appear to use Compartmentalization of Toll-like receptors (TLRs) in intestinal specific pathogen pattern recognition receptors such as the Toll-like epithelial cells (IECs) regulates distinct immune responses to receptors (TLRs) to balance immune tolerance and immune microbes; however, the specific cellular machinery that controls response, depending on specific cellular localization of the receptors this mechanism has not been fully identified. Here we provide (Abreu, 2010). In cultured human colon epithelial cells, bacterial genetic evidences that the recycling endosomal compartment in cytosine-guanine (CpG) stimulation of apically localized TLR9 from enterocytes maintains a homeostatic TLR9 intracellular distribu- the luminal side induced tolerance to subsequent microbial agonist tion, supporting mucosal tolerance to normal microbiota. Genetic stimulations, whereas basolateral stimulation of TLR9 provoked ablation of a recycling endosome resident small GTPase, Rab11a,a NF-jB activation and cytokine production (Lee et al, 2006). In gene adjacent to a Crohn’s disease risk locus, in mouse IECs and in contrast, the exclusive basolateral localization of TLR5 in IECs Drosophila midgut caused epithelial cell-intrinsic cytokine produc- appeared to facilitate this sensor to only respond to the invaded tion, inflammatory bowel phenotype, and early mortality. Unlike bacterial flagellin protein after barrier function impairment (Gewirtz wild-type controls, germ-free Rab11a-deficient mouse intestines et al, 2001; Rhee et al, 2005). Furthermore, apical localization of failed to tolerate the intraluminal stimulation of microbial agon- TLR4 was described in human colon epithelial cell lines, and this ists. Thus, Rab11a endosome controls intestinal host-microbial receptor changed its subcellular localization upon ligand stimulation homeostasis at least partially via sorting TLRs. (Cario et al, 2002). In the small intestine, TLR4 signaled from endo- somes in response to its internalized ligand lipopolysaccharide Keywords enterocyte; inflammation; intestinal homeostasis; Rab11a; Toll-like (LPS), allowing differentiation between various types of LPS (Hornef receptor et al, 2003). In addition to receptor compartmentalization, proteo- Subject Categories Cell Adhesion, Polarity & Cytoskeleton; Immunology lytic cleavage of TLR9 in endolysosomal compartment provides DOI 10.15252/embj.201487888 | Received 11 January 2014 | Revised 12 June another crucial control for proper receptor activation in immune 2014 | Accepted 13 June 2014 | Published online 25 July 2014 cells (Ewald et al, 2008; Park et al, 2008). However, the absolute The EMBO Journal (2014) 33: 1882–1895 requirement of this proteolytic processing and the role of cleaved N-terminal domain for TLR9 activation are still under intensive studies (Peter et al, 2009; Mouchess et al, 2011; Onji et al, 2013). Introduction Since adverse activation of microbial sensors could elicit unwanted immune responses driving intestinal pathogenesis A finely tuned immuno-surveillance system that exquisitely (Leaphart et al, 2007; Fukata et al, 2011), there is a clear imperative balances immuno-responsive and immuno-repressive activities is to understand the IEC-intrinsic sorting units controlling the proper necessary for microbe–host homeostasis in animal tissues. Genetic compartmentalization and activation of TLRs. A recently reported and environmental factors that disrupt this balance may underlie Crohn’s disease risk locus at chromosome 15q22 (dbSNP ID: various immunological disorders including the inflammatory bowel rs17293632) is adjacent to the human RAB11A (Franke et al, 2010). diseases (IBDs). In mammals, the postnatal intestinal epithelial cells This gene encodes a small GTPase representing one of the most (IECs), after transitioning from a relatively germ-free fetal environ- prominent components of a special endosomal subpopulation—the ment, immediately interact with enteric microbes and participate in recycling endosome (Goldenring, 2013). Studies in cultured cell 1 Department of Biological Sciences, Rutgers University, Newark, NJ, USA 2 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA 3 Experimental Surgery, Vanderbilt University Medical Center, Nashville, TN, USA 4 Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ, USA 5 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA *Corresponding author. Tel: +1 973 353 5523; Fax: +1 973 353 5518; E-mail: [email protected] 1882 The EMBO Journal Vol 33 |No17 | 2014 ª 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license Published online: July 24, 2014 Shiyan Yu et al Rab11 controls intestinal homeostasis The EMBO Journal lines suggested that the RAB11A endosome engages in intense of enterocytes and three intestinal secretory cell lineages was D membrane recycling and sorting, and connect the endo- and exo- unaffected in Rab11a IEC mice (enterocytes and goblet cells shown cytic pathways (van Ijzendoorn, 2006). In cultured human colonic in Fig 1F, paneth and enteroendocrine cells in Supplementary Fig epithelial cells, RAB11A depletion caused abnormal lumen forma- S3A). Rab11a-deficient enterocytes were still capable to elaborate tion. In mouse intestines, Rab11a expression is increased in IECs apical brush borders (Supplementary Fig S3B). Therefore, Rab11a during cellular differentiation and maturation (Gao & Kaestner, deletion did not appear to disrupt the differentiation of major intesti- 2010). Here, we used genetic and biochemical approaches to show nal cell lineages. However, the epithelial hyperplasia, dysplasia, and that Rab11a endosomal compartment maintains homeostatic TLR9 immune cell infiltration continued to be present in older survivor D compartmentalization at steady-state conditions. By doing so, Rab11a IEC mice (5 months old shown in Supplementary Fig S1B), Rab11a appeared to prevent unwanted pro-inflammatory stimuli. which showed high histopathology scores indicative of intestinal Genetic and cell type-specific inactivation of Rab11a in mouse and inflammation (Fig 1H) (Adolph et al, 2013). Finally, tamoxifen Drosophila IECs midgut caused aberrant NF-jB activation, inflam- induced deletion of Rab11a specifically in Lgr5+ intestinal epithelial matory cytokine production, and IBD phenotypes. Removal of stem cells (IESCs, or crypt-based columnar cells, CBCs) in Rab11afl/fl; microbial ligands (germ-free) alleviated these phenotypes in the Lgr5EGFP-IRES-CreER mice increased the proliferation of both the Lgr5+ Δ mutants. Unlike wild-type controls, germ-free Rab11a IEC mice and the transit-amplifying cells (Fig 1I). No immediate cell death failed to tolerate intraluminal perfusion of microbial TLR agonists. was triggered by inducible Rab11a deletions (data not shown). Our data suggested that Rab11a controls intestinal microbial toler- To identify the mechanisms underlying the above pathological ance at least partially via sorting TLRs. abnormalities, we performed microarray analysis on neonatal (post- natal day 3, P3) mouse intestines using four independent pairs of D RNA samples from Rab11a IEC and wild-type littermates (Fig 2A). Results Inflammatory genes encoding cytokines, chemokines, defensins, and anti-microbial peptides were significantly upregulated as the D Rab11a ablation in intestinal epithelia causes inflammation most enriched gene category in Rab11a IEC intestines (Fig 2B and C). Overlapping analyses revealed that 79 and 138 upregulated tran- D To study the contribution of Rab11a recycling endosome to intesti- scripts in Rab11a IEC
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