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The Antimicrobial Protein Rnase 7 of the Airway Epithelium Through Basal Cells Contribute to Innate Immunity of the Airway Epithelium through Production of the Antimicrobial Protein RNase 7 This information is current as Gimano D. Amatngalim, Yolanda van Wijck, Yvonne de of September 23, 2021. Mooij-Eijk, Renate M. Verhoosel, Jürgen Harder, Annemarie N. Lekkerkerker, Richard A. J. Janssen and Pieter S. Hiemstra J Immunol 2015; 194:3340-3350; Prepublished online 23 February 2015; Downloaded from doi: 10.4049/jimmunol.1402169 http://www.jimmunol.org/content/194/7/3340 Supplementary http://www.jimmunol.org/content/suppl/2015/02/21/jimmunol.140216 http://www.jimmunol.org/ Material 9.DCSupplemental References This article cites 47 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/194/7/3340.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Basal Cells Contribute to Innate Immunity of the Airway Epithelium through Production of the Antimicrobial Protein RNase 7 Gimano D. Amatngalim,* Yolanda van Wijck,* Yvonne de Mooij-Eijk,* Renate M. Verhoosel,* Jurgen€ Harder,† Annemarie N. Lekkerkerker,‡,1 RichardA.J.Janssen,‡ and Pieter S. Hiemstra* Basal cells play a critical role in the response of the airway epithelium to injury and are recently recognized to also contribute to epithelial immunity. Antimicrobial proteins and peptides are essential effector molecules in this airway epithelial innate immunity. However, little is known about the specific role of basal cells in antimicrobial protein and peptide production and about the reg- ulation of the ubiquitous antimicrobial protein RNase 7. In this study, we report that basal cells are the principal cell type producing Downloaded from RNase 7 in cultured primary bronchial epithelial cells (PBEC). Exposure of submerged cultured PBEC (primarily consisting of basal cells) to the respiratory pathogen nontypeable Haemophilus influenzae resulted in a marked increase in expression of RNase 7, although this was not observed in differentiated air–liquid interface cultured PBEC. However, transient epithelial injury in air– liquid interface–cultured PBEC induced by cigarette smoke exposure led to epidermal growth factor receptor–mediated expres- sion of RNase 7 in remaining basal cells. The selective induction of RNase 7 in basal cells by cigarette smoke was demonstrated using confocal microscopy and by examining isolated luminal and basal cell fractions. Taken together, these findings demonstrate http://www.jimmunol.org/ a phenotype-specific innate immune activity of airway epithelial basal cells, which serves as a second line of airway epithelial defense that is induced by airway epithelial injury. The Journal of Immunology, 2015, 194: 3340–3350. ucosal epithelial cells are an essential component of other epithelial phenotypes upon injury to restore the airway epi- the host defense barrier against microbial pathogens. thelial barrier. The basolateral localized BCs are shielded from M In the lung, a pseudostratified layer of airway epithe- direct microbial contact by the overlying LCs in intact airway lial cells provides this host defense via a passive barrier function epithelium. However, airway epithelial injury caused by disrup- but also active innate immune defense mechanisms (1, 2). These tion of the epithelial barrier because of the loss of cell–cell contact by guest on September 23, 2021 mechanisms are primarily executed by airway epithelial luminal or shedding of LCs after extensive injury may increase microbial cells (LCs), mainly composed of ciliated and secretory cells, exposure. This may enhance the vulnerability of BCs and under- which facilitate for instance mucociliary clearance, defense me- lying tissues to respiratory infections. Recently, Byer et al. (10) diated by periciliary tethered mucins, production of innate immune demonstrated selective expression of the proinflammatory medi- mediators upon pathogen recognition, and Ig transcytosis toward the ator IL-33 by a subpopulation of BCs in patients with chronic airway surface liquid (3–6). In contrast to LCs, it has been largely obstructive pulmonary disease. On the basis of this observation, unexplored whether airway epithelial basal cells (BCs) have an innate we speculate that BCs might display other unique innate immune immune function. BCs are characterized as epithelial progenitor cells responses, which act as a second line of airway epithelial host and defined based on the expression of p63 and cytokeratin 5 defense in addition to the activity of LCs. (KRT5) (7–9). BCs display a low turnover at normal homeostatic Antimicrobial proteins and peptides (AMPs) are important in- conditions but rapidly expand and subsequently differentiate toward nate immune mediators involved in airway epithelial host defense (11). AMPs display direct antimicrobial activity against bacteria, *Department of Pulmonology, Leiden University Medical Center, 2300 RC Leiden, viruses, and fungi but also exhibit immunomodulatory and wound the Netherlands; †Department of Dermatology, University Hospital Schleswig- Holstein, 24105 Kiel, Germany; and ‡Galapagos BV, 2333 CR Leiden, the Netherlands healing properties (12, 13). The antimicrobial RNase 7 is a secreted RNase A family member displaying antimicrobial activity toward a 1Current address: Development Sciences, Genentech, Inc., South San Francisco, CA. range of pathogens, including the respiratory pathogen Pseudomonas Received for publication August 22, 2014. Accepted for publication January 25, 2015. aeruginosa (14–16). Previous studies exploring the regulation of This work was supported by an unrestricted research grant from Galapagos BV. RNase 7 expression in skin, urinary tract, and ocular surface epithelial Address correspondence and reprint requests to Gimano D. Amatngalim, Department cells, demonstrated increased RNase 7 expression upon stimulation of Pulmonology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, with microbes, microbial compounds, and proinflammatory cytokines 2300 RC Leiden, the Netherlands. E-mail address: [email protected] (17–19). Moreover, mechanical injury and UV radiation induce ex- The online version of this article contains supplemental material. pression of RNase 7 in keratinocytes (20, 21), demonstrating that Abbreviations used in this article: ALI-PBEC, air–liquid interface–cultured PBEC; epithelial injury is a potent inducer of RNase 7 expression. Although AMP, antimicrobial protein and peptide; BC, basal cell; EGFR, epidermal growth factor receptor; hBD-2, human b-defensin-2; KRT5, cytokeratin 5; LC, luminal cell; RNase 7 expression has been detected in cultured airway epithelial LCN2, lipocalin 2; LDH, lactate dehydrogenase; NTHi, nontypeable Haemophilus cells (14), it is currently unknown how RNase 7 expression is regu- influenzae; PBEC, primary bronchial epithelial cell; qPCR, quantitative real-time lated in these cells. PCR; S-PBEC, submerged cultured PBEC; TEER, transepithelial electrical resistance. In this paper, we provide evidence that BCs are the principal cell Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 producing RNase 7 in cultured human primary bronchial epithelial www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402169 The Journal of Immunology 3341 cells (PBEC) upon exposure to the respiratory pathogen nontypeable for the indicated period of times. UV-inactivated NTHi or Pam3CSK4 Haemophilus influenzae (NTHi) and epithelial barrier disruption (InvivoGen, San Diego, CA) was administered in a volume of 100 mlinPBS caused by cigarette smoke exposure. Submerged cultured undif- at the apical surface of ALI-PBEC or added to the culture medium when stimulating S-PBEC. In the experiment examining cell signaling pathways ferentiated PBEC (S-PBEC), primarily consisting of BCs, but and the effect of rTGF-a, ALI-PBEC were starved for 24 h before the ex- not mucociliary differentiated air–liquid interface–cultured PBEC periment with supplemented B/D medium earlier described, without 0.4% (ALI-PBEC), expressed RNase 7 upon stimulation with UV- [w/v] bovine pituitary extract, 0.5 ng/ml human hEGF, and 1 mg/ml BSA. To inactivated NTHi. Transient epithelial injury induced by whole examine cell signaling pathways, the following chemical inhibitors were applied: AG1478, anti-EGFR neutralizing Ab, and U0125 (all Calbiochem, cigarette smoke coincides with epidermal growth factor receptor Darmstadt, Germany). Inhibitors were added into the basal culture medium (EGFR)-dependent expression of RNase 7 in ALI-PBEC, and this and preincubated for 1 h prior to smoke exposure. Stimulation of ALI-PBEC expression is specifically observed in BCs. These findings dem- with rTGF-a (PeproTech, Rocky Hill,
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