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Epithelial Cells Inflammasome Activation in Intestinal Integrin Integrin-Mediated First Signal for Inflammasome Activation in Intestinal Epithelial Cells This information is current as Josephine Thinwa, Jesus A. Segovia, Santanu Bose and of October 3, 2021. Peter H. Dube J Immunol 2014; 193:1373-1382; Prepublished online 25 June 2014; doi: 10.4049/jimmunol.1400145 http://www.jimmunol.org/content/193/3/1373 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/06/25/jimmunol.140014 Material 5.DCSupplemental http://www.jimmunol.org/ References This article cites 53 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/193/3/1373.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 3, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Integrin-Mediated First Signal for Inflammasome Activation in Intestinal Epithelial Cells Josephine Thinwa,* Jesus A. Segovia,*,† Santanu Bose,*,†,1 and Peter H. Dube*,† How intestinal epithelial cells (IECs) recognize pathogens and activate inflammasomes at intestinal surfaces is poorly understood. We hypothesized that IECs use integrin receptors to recognize pathogens and initiate inflammation within the intestinal tract. We find that IECs infected with Yersinia enterocolitica, an enteric pathogen, use b1 integrins as pathogen recognition receptors detecting the bacterial adhesin invasin (Inv). The Inv–integrin interaction provides the first signal for NLRP3 inflammasome activation with the type three secretion system translocon providing the second signal for inflammasome activation, resulting in release of IL-18. During infection, Yersinia employs two virulence factors, YopE and YopH, to counteract Inv-mediated integrin- dependent inflammasome activation. Furthermore, NLRP3 inflammasome activation in epithelial cells requires components of the focal adhesion complex signaling pathway, focal adhesion kinase, and rac1. The binding of Inv to b1 integrins rapidly induces IL-18 mRNA expression, suggesting integrins provide a first signal for NLRP3 inflammasome activation. These data suggest Downloaded from integrins function as pathogen recognition receptors on IECs to rapidly induce inflammasome-derived IL-18–mediated responses. The Journal of Immunology, 2014, 193: 1373–1382. ucosal surfaces are exquisitely sensitive to inflamma- two signals; the first signal results from PAMP recognition and tion-mediated immune pathologies, necessitating strict leads to the increased expression of the inflammasome compo- M regulation of inflammatory responses (1, 2). To mini- nents and substrate cytokines; various cellular insults such as pore http://www.jimmunol.org/ mize unwanted inflammation, epithelial cells in environments with formation can provide the second signal for the NLRP3 inflam- high microbial burdens, such as the intestine, selectively express masome, resulting in caspase-1 cleavage and cytokine release. In- pathogen-associated molecular pattern (PAMP) receptors (PAMPR) flammasome activation is best studied in macrophages; however, on the basolateral surface or in endosomal compartments (3). Ad- several cell types can produce IL-1b and IL-18. Intestinal epi- ditionally, production of inflammatory cytokines IL-1b and IL-18 is thelial cells (IECs) do not express IL-1b, but they do express pro– tightly regulated transcriptionally by PAMPRs and posttransla- IL-18, and IL-18 derived from IECs and hematopoietic cells is tionally by the inflammasome (4–7). known to protect against colitis and colorectal cancer in mouse Inflammasomes are macromolecular machines that promote models (9–11). by guest on October 3, 2021 activation of caspase-1 in response to PAMP molecules, cellular The intestinal epithelium resides in a unique immunological en- stress, or cellular damage (8). Ultimately, inflammasome activation vironment, where it is potentially in contact with microorganisms leads to the initiation of inflammatory signaling through cleavage constituting the normal flora. Additionally, the intestine is a major of pro–IL-1b and IL-18 to their active forms and secretion of portal for infectious diseases, suggesting IECs evolved mecha- these cytokines from the cell. Inflammasomes are usually com- nisms to distinguish between innocuous flora and dangerous posed of a sensor protein from the nucleotide-binding domain and pathogens (1). The mechanisms underlying inflammasome activation leucine-rich repeat protein family (NLR), an adaptor protein such in response to infection of IECs are not understood. as apoptosis-associated speck-like protein containing a CARD, and However, a critical step in the pathogenesis of food-borne bac- caspase-1. The activation of inflammasomes is thought to involve terial pathogens is attachment or attachment and invasion of IECs (12). Some of the best-characterized invasive pathogens of the in- *Department of Microbiology and Immunology, University of Texas Health Science testine are Yersinia enterocolitica and the closely related Yersinia Center, San Antonio, TX 78229; and †Center for Airway Inflammation Research, pseudotuberculosis. University of Texas Health Science Center, San Antonio, TX 78229 Y. enterocolitica is a zoonotic bacterial food-borne pathogen of 1 Current address: Department of Veterinary Microbiology and Pathology, College of humans causing terminal ileitis, enterocolitis, and mesenteric Veterinary Medicine, Washington State University, Pullman, WA. lymphadenitis (13, 14). To attach to and invade intestinal tissues, Received for publication January 17, 2014. Accepted for publication May 20, 2014. Yersinia expresses an adhesin called invasin (Inv) (15, 16). Inv This work was supported by National Institutes of Health Grants AI067716 and binds to b integrins predominantly expressed on microfold epi- AI060789 (to P.H.D.), AI083387 (to S.B.), and 5T32 AI007271 (to J.A.S.), and a 1 Translational Science Training Fellowship (to J.T.). thelial cells overlying Peyer’s patches (PP) (17). Inv-mediated Address correspondence and reprint requests to Dr. Peter H. Dube, University of integrin binding facilitates invasion of the intestinal epithelium Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229. and PP colonization. Once Y. enterocolitica establishes infection E-mail address: [email protected] of the PP, it is an extracellular pathogen that utilizes numerous The online version of this article contains supplemental material. virulence factors to modulate host responses to infection (18, 19). Abbreviations used in this article: au, arbitrary unit; FAK, focal adhesion kinase; IEC, Y. enterocolitica encodes virulence factors on both the chro- intestinal epithelial cell; Inv, invasin; LB, Luria–Bertani; MOI, multiplicity of infec- tion; PAMP, pathogen-associated molecular pattern; PAMPR, PAMP receptor; PP, mosome and the 70-kb virulence plasmid, pYV (14, 19). pYV Peyer’s patch; qRT-PCR, quantitative RT-PCR; shRNA, short hairpin RNA; siRNA, encodes several effector toxins and a type three secretion system small interfering RNA; TTSS, type three secretion system; Yop, Yersinia outer pro- (TTSS) that provides a conduit to secrete these effectors from the tein. bacterial cytosol directly into the host cell cytoplasm (19, 20). The Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 TTSS translocon proteins form a pore in the host cell membrane www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400145 1374 INFLAMMASOME ACTIVATION IN INTESTINAL EPITHELIUM serving as a signal for NLRP3 inflammasome activation and in- nlrp3, and GAPDH, with the resulting product fractionated by agarose gel flammatory cytokine secretion from macrophages (21–24). The electrophoresis. effectors known as Yersinia outer proteins (Yops) are mostly Cells and infection enzymes; for example, YopH is a protein tyrosine phosphatase that dephosphorylates focal adhesion kinase (FAK), p130 cas, and Human enterocyte cell line Caco-2 was cultured at 37˚C with 5% CO2 in 20% FBS MEM. For infections, cells were grown to confluence (4 d) in other components of the focal adhesion complex to disrupt the 12- or 6-well dishes. Yersinia (Supplemental Table II) were grown over- actin cytoskeleton in epithelial cells (25–30). YopE, a GTPase- night in Luria–Bertani (LB) medium containing 20 mg/ml nalidixic acid at activating protein, targets signaling of the small G proteins Rac, 28˚C. The cultures were then diluted 1:100 into fresh media and grown Rho, and Cdc42 (31). Both YopH and YopE act together to inhibit at 37˚C for 2 h. Salmonella were grown overnight in LB medium 37˚C, diluted into fresh LB medium, and grown standing for 3.5 h at 37˚C. All b1 integrin signaling. YopP/J, a protease and protein acetylase, has bacteria were washed with PBS and diluted into OPTI-MEM at an OD of been implicated in modulation of the
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