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Ischemia Regulates NK Cell Recruitment in Kidney TLR2 TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia−Reperfusion Injury This information is current as Hye J. Kim, Jong S. Lee, Ahra Kim, Sumi Koo, Hee J. Cha, of September 29, 2021. Jae-A Han, Yoonkyung Do, Kyung M. Kim, Byoung S. Kwon, Robert S. Mittler, Hong R. Cho and Byungsuk Kwon J Immunol 2013; 191:2657-2664; Prepublished online 31 July 2013; doi: 10.4049/jimmunol.1300358 Downloaded from http://www.jimmunol.org/content/191/5/2657 Supplementary http://www.jimmunol.org/content/suppl/2013/07/31/jimmunol.130035 Material 8v1.DC1 http://www.jimmunol.org/ References This article cites 97 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/191/5/2657.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 29, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia–Reperfusion Injury Hye J. Kim,*,1 Jong S. Lee,*,†,1 Ahra Kim,‡ Sumi Koo,* Hee J. Cha,*,x Jae-A Han,{ Yoonkyung Do,{ Kyung M. Kim,†,‖ Byoung S. Kwon,# Robert S. Mittler,‡,** Hong R. Cho,*,†† and Byungsuk Kwon*,‡ Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia–reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L2/2 TECs into the kidney Downloaded from capsule of TLR22/2 mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI. The Journal of Immunology, 2013, 191: 2657–2664. http://www.jimmunol.org/ nflammation is a physiological response that manages both recognize a number of endogenous molecules released from in- external and internal danger signals and restores homeostasis jured cells (3). Evidence of TLR involvement in kidney ischemia– I (1). Sterile inflammation, caused by tissue damage without reperfusion injury (IRI) is accumulating (4–8). Endogenous TLR2 infection, can occur in conditions such as trauma, ischemia, is- and TLR4 ligands are released from the tubular epithelium after chemia and reperfusion (IR), or cellular malfunction (1–3). Sen- IR (9–11). Tubular epithelial cells (TECs) seem to play a central sors that recognize molecules released by damaged tissues induce role in initiating kidney IRI, as they express TLR2 and TLR4. inflammation through signaling that results in the production of Additionally, a parenchymal cell deficiency of either gene dramat- by guest on September 29, 2021 inflammatory mediators by tissue-specific immune cells or pa- ically limits kidney injury following IR and diminishes the asso- renchymal cells (1). TLRs are the most well-known sensors and ciated intrarenal inflammation (4, 5). In addition to this autocrine mechanism, endogenous TLR ligands may act on other cell types such as endothelial cells and innate immune cells in a paracrine *Biomedical Research Center, Ulsan University Hospital, School of Medicine, Uni- manner to promote IRI-associated acute inflammation. TLR2 or versity of Ulsan, Ulsan 682-714, Korea; †Department of Internal Medicine, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan 682-714, Korea; TLR4 signaling results in proinflammatory cytokine and chemokine x ‡School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea; Depart- production, but little is known regarding how the TLR inflammatory ment of Pathology, Ulsan University Hospital, School of Medicine, University of Ulsan, Ulsan 682-714, Korea; {School of Nano-Bioscience and Chemical Engineer- cascade is triggered by cell–cell interactions among TECs, stromal ing, Ulsan National Institute of Science and Technology, Ulsan 689-798, Korea; cells, endothelial cells, and infiltrating leukocytes after IR. ‖ Department of Internal Medicine, Dongnam Institute of Radiological and Medical We have previously identified an inflammatory loop between Sciences, Busan 619-953, Korea; #Division of Cell and Immunobiology, Research and Development Center for Cancer Therapeutics, National Cancer Center, Ilsan 410- TECs and inflammatory cells during kidney IRI (12). NK cells 769, Korea; **Department of Surgery, Emory Vaccine Center, Emory University infiltrate the kidney early after IR and approach the tubular epithe- †† School of Medicine, Atlanta, GA 30322; and Department of Surgery, Ulsan Uni- lium across the basement membrane, which is rapidly destroyed versity Hospital, School of Medicine, University of Ulsan, Ulsan 680-749, Korea by IRI (12, 13). Infiltrating NK cells in turn stimulate TECs 1H.J.K. and J.S.L. contributed equally to this work. to produce CXCR2 chemokines by stimulating CD137 ligand Received for publication February 6, 2013. Accepted for publication June 27, 2013. (CD137L) signaling and inducing neutrophil migration (12). Re- This work was supported by grants from the National Research Foundation of Korea cent studies have revealed a positive feedback among dendritic funded by the Ministry of Education, Science and Technology (Grants NRF-2011- 0012596, BRL2009-0087350, and 2009-0094050) and by Chong Keun Dang Phar- cells, NKT cells, and neutrophils to amplify acute inflammation maceutical Corp., Seoul, Korea. leading to kidney IRI (14). Therefore, the events following IR and Address correspondence and reprint requests to Prof. Byungsuk Kwon or Dr. Hong the complex network of stromal cells, endothelial cells, TECs, and R. Cho, School of Biological Sciences, University of Ulsan, San29 Mukeo-dong, immune cells should be defined to better understand IRI-asso- Nam-ku, Ulsan 680-749, Korea (B.K.) or Department of Surgery, Ulsan University Hospital, University of Ulsan, Ulsan 682-714, Korea (H.R.C.). E-mail addresses: bkwon@ ciated inflammation. mail.ulsan.ac.kr (B.K.) or [email protected] (H.R.C.) Currently, the regulation of signals that recruit NK cells fol- The online version of this article contains supplemental material. lowing IRI is not well understood. The aim of this study was to Abbreviations used in this article: BUN, blood urea nitrogen; CD137L, CD137 determine the mechanism of NK cell recruitment to the kidney af- ligand; HMGB1, high mobility group box 1; IR, ischemia and reperfusion; IRI, ter IR. We found that TECs produced CCR5 chemokines, which ischemia–reperfusion injury; TEC, tubular epithelial cell; WT, wild-type. are required for NK cell chemotaxis, early after IR in a TLR2- Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 dependent manner. Moreover, NK cell and neutrophil recruit- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300358 2658 NK CELL RECRUITMENT BY TLR2 SIGNALING ment by TECs was a sequential and independent event. These sues were passed through a 40-mm cell strainer (BD Falcon) using the results indicate that epithelial cells actively regulate sterile tissue rubber end of a 1-ml syringe plunger, and a cell suspension was obtained inflammation more than was previously recognized. via centrifugation at 1200 rpm for 10 min. Cells were washed in PBS containing 2% BSA and suspended in 36% Percoll (Amersham Pharmacia Biotech). The suspension was gently overlaid onto 72% Percoll and Materials and Methods centrifuged at 2000 rpm at room temperature for 30 min. Cells were re- Mice trieved from the Percoll interface and washed twice in DMEM medium and once with staining buffer (PBS containing 0.2% BSA and 0.1% so- 2 2 2 2 2 2 2 2 CD137 / , CD137L / , CCR5 / , and TLR2 / C57BL/6 mice were dium azide). maintained in a specific pathogen-free facility and used between 7 and 8 wk of age. Wild-type (WT) C57BL/6 mice were purchased from Orient. Flow cytometry Animal studies were approved by the University of Ulsan Animal Care and Prepared
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