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• W2799994211 abstract "Eosinophils are effector cells in allergy that are both recruited from circulation and develop via in situ hematopoiesis in the local tissue environment.E1Radinger M. Bossios A. Sjostrand M. Lu Y. Malmhall C. Dahlborn A.K. et al.Local proliferation and mobilization of CCR3(+) CD34(+) eosinophil-lineage-committed cells in the lung.Immunology. 2011; 132: 144-154Crossref PubMed Scopus (30) Google Scholar, E2Southam D.S. Widmer N. Ellis R. Hirota J.A. Inman M.D. Sehmi R. Increased eosinophil-lineage committed progenitors in the lung of allergen-challenged mice.J Allergy Clin Immunol. 2005; 115: 95-102Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, E3Lee J.J. Jacobsen E.A. McGarry M.P. Schleimer R.P. Lee N.A. Eosinophils in health and disease: the LIAR hypothesis.Clin Exp Allergy. 2010; 40: 563-575Crossref PubMed Scopus (245) Google Scholar Although eosinophil depletion in tissues is a highly sought-after therapeutic strategy in treating allergic disease, little is known about the role of tissue factors in promoting eosinophilia. In disease, tissue eosinophils typically encounter provisional extracellular matrix (ECM) glycoproteins, such as periostin, versican, thrombospondins, and tenascins.1Wells A. Nuschke A. Yates C.C. Skin tissue repair: matrix microenvironmental influences.Matrix Biol. 2016; 49: 25-36Crossref PubMed Scopus (90) Google Scholar Particularly, eosinophil expansion in tissues strongly correlates with tenascin-C (TNC) deposition.2Karjalainen E.M. Lindqvist A. Laitinen L.A. Kava T. Altraja A. Halme M. et al.Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.Respir Med. 2003; 97: 1045-1051Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, E4Nakahara H. Gabazza E.C. Fujimoto H. Nishii Y. D'Alessandro-Gabazza C.N. Bruno N.E. et al.Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse.Eur J Immunol. 2006; 36: 3334-3345Crossref PubMed Scopus (56) Google Scholar Although highly restricted in healthy adult tissues, TNC is strongly expressed de novo during wound healing and pathologic tissue remodeling. TNC is a hexabrachion featuring epidermal growth factor–like repeats, fibronectin type III (FN3)-like repeats, and a fibrinogen-like globe that interface integrins and other matrix components in tissues.3Midwood K.S. Chiquet M. Tucker R.P. Orend G. Tenascin-C at a glance.J Cell Sci. 2016; 129: 4321-4327Crossref PubMed Scopus (240) Google Scholar, E5Pas J. Wyszko E. Rolle K. Rychlewski L. Nowak S. Zukiel R. et al.Analysis of structure and function of tenascin-C.Int J Biochem Cell Biol. 2006; 38: 1594-1602Crossref PubMed Scopus (44) Google Scholar, E6De Laporte L. Rice J.J. Tortelli F. Hubbell J.A. Tenascin C promiscuously binds growth factors via its fifth fibronectin type III-like domain.PLoS One. 2013; 80: e62076Crossref Scopus (85) Google Scholar Importantly, TNC is a known hematopoietic niche component in the bone marrow stroma.4Nakamura-Ishizu A. Okuno Y. Omatsu Y. Okabe K. Morimoto J. Uede T. et al.Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration.Blood. 2012; 119: 5429-5437Crossref PubMed Scopus (103) Google Scholar, E7Ohta M. Sakai T. Saga Y. Aizawa S. Saito M. Suppression of hematopoietic activity in tenascin-C-deficient mice.Blood. 1998; 91: 4074-4083PubMed Google Scholar Moreover, exposing naive murine eosinophils to TNC-enriched provisional matrices significantly upregulates the gene expression of immaturity markers (Ly6a [Sca-1], CD34) and suppresses IL-5Rα (IL5ra [CD125]) expression, as determined by RNA-Seq (our unpublished data, 2018). This led us to hypothesize that TNC represents a factor in the provisional allergic tissue microenvironment that could potentially support in situ eosinophil progenitor expansion. In support, we show that in murine bone marrow–derived cultures, TNC (1) 3-fold expanded the available Lin−Sca1+ early precursor pool; (2) significantly downregulated IL-5Rα expression on Lin−CD45+c-kit+ cells during the eosinophil lineage commitment phase; and (3) served as a reversible block of eosinophil maturation, as TNC withdrawal from cultures rescued maturation and increased the final eosinophil yield. Furthermore, we show that TNC knockout mice lack in situ lung expansion of Lin−c-kit+CD34+ common myeloid progenitors and Lin−Siglec-F+Sca-1+ cells in an allergic inflammation model, while exhibiting accelerated maturation of lung eosinophils ex vivo. Adding TNC to lung homogenates cultured in IL-5 ex vivo suppressed eosinophil maturation in a manner consistent with the TNC eosinophil maturation block in bone marrow–derived cultures. Experimental procedures and additional references can be found in this article's Online Repository at www.jacionline.org. Bone marrow–derived eosinophil cultures supplemented with TNC significantly expanded the Lin−Sca-1+ early precursor pool compared with controls (Fig 1, B-D; see Fig E1 in this article's Online Repository at www.jacionline.org). Maturation suppression was evidenced by constitutive Sca-1 expression (hematopoietic progenitor/stem cell marker) at all time points in TNC culture (Fig 1, D). Terminal IL-5–driven eosinophil differentiation and maturation was significantly suppressed by TNC addition, as determined by flow cytometry (Fig 1, B and C). In comparison with control samples expressing only Siglec-F, TNC-treated cultures on day 15 had a substantial proportion of eosinophils expressing both Siglec-F (eosinophil marker) and Sca-1 (Fig 1, C). Compared with controls, differential staining at TNC culture end points revealed morphology characteristic for class III eosinophil progenitor cells,E12Lee N.A. McGarry M.P. Larson K.A. Horton M.A. Kristensen A.B. Lee J.J. Expression of IL-5 in thymocytes/T cells leads to the development of a massive eosinophilia, extramedullary eosinophilopoiesis, and unique histopathologies.J Immunol. 1997; 158: 1332-1344PubMed Google Scholar featuring a lack of distinct eosin staining and nonsegmented nuclei (Fig 1, B). TNC may have a direct effect on maturing eosinophils via the binding of integrin-binding and fibronectin (and other ECM)-binding repeats within its FN3 domain,3Midwood K.S. Chiquet M. Tucker R.P. Orend G. Tenascin-C at a glance.J Cell Sci. 2016; 129: 4321-4327Crossref PubMed Scopus (240) Google Scholar which was specifically presented to eosinophils in our cultures. Among integrins, α9β1 integrin specifically binds the AEIDGIEL sequence in the FN3 TNC domain,5Yokosaki Y. Matsuura N. Higashiyama S. Murakami I. Obara M. Yamakido M. et al.Identification of the ligand binding site for the integrin alpha9 beta1 in the third fibronectin type III repeat of tenascin-C.J Biol Chem. 1998; 273: 11423-11428Crossref PubMed Scopus (137) Google Scholar, E13Tucker R.P. Chiquet-Ehrismann R. Tenascin-C: its functions as an integrin ligand.Int J Biochem Cell Biol. 2015; 65: 165-168Crossref PubMed Scopus (75) Google Scholar and this integrin expression on human hematopoietic stem and progenitor cells was found to regulate cell proliferation and differentiation.6Schreiber T.D. Steinl C. Essl M. Abele H. Geiger K. Muller C.A. et al.The integrin alpha9beta1 on hematopoietic stem and progenitor cells: involvement in cell adhesion, proliferation and differentiation.Haematologica. 2009; 94: 1493-1501Crossref PubMed Scopus (58) Google Scholar These findings are consistent with reports of TNC and other provisional ECM proteins regulating hematopoiesis.E9Choi J.S. Harley B.A. Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells.Sci Adv. 2017; 3: e1600455Crossref PubMed Scopus (85) Google Scholar, E10Klamer S. Voermans C. The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment.Cell Adh Migr. 2014; 8: 563-577Crossref PubMed Scopus (61) Google Scholar, E11Chitteti B.R. Bethel M. Voytik-Harbin S.L. Kacena M.A. Srour E.F. In vitro construction of 2D and 3D simulations of the murine hematopoietic niche.Methods Mol Biol. 2013; 1035: 43-56Crossref PubMed Scopus (6) Google Scholar TNC sustains hematopoietic regeneration after bone marrow ablation, which is dependent on FN3 domain binding.4Nakamura-Ishizu A. Okuno Y. Omatsu Y. Okabe K. Morimoto J. Uede T. et al.Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration.Blood. 2012; 119: 5429-5437Crossref PubMed Scopus (103) Google Scholar Mice lacking TNC show reduced bone marrow colony-forming capacity and hematopoietic cell production. Within the bone marrow environment, fibronectin affects progenitor fate decisions via the FN3 domain binding.7Malara A. Gruppi C. Celesti G. Romano B. Laghi L. De Marco L. et al.Brief report: alternative splicing of extra domain A (EIIIA) of fibronectin plays a tissue-specific role in hematopoietic homeostasis.Stem Cells. 2016; 34: 2263-2268Crossref PubMed Scopus (8) Google Scholar Hyaluronic acid scaffolds are sufficient to maintain long-term cultures of CD34+ hematopoietic cells obtained from human cord blood.8Demange E. Kassim Y. Petit C. Buquet C. Dulong V. Cerf D.L. et al.Survival of cord blood haematopoietic stem cells in a hyaluronan hydrogel for ex vivo biomimicry.J Tissue Eng Regen Med. 2013; 7: 901-910Crossref PubMed Scopus (16) Google Scholar Identifying specific integrin-matrix interactions regulatory for in situ hematopoiesis of eosinophil progenitors is a subject of future studies by our group. Next, we showed that TNC suppresses eosinophil progenitor differentiation by suppressing IL-5Rα expression on Lin−CD45+c-kit+ precursor cells. By flow cytometry, IL-5Rα expression on Lin−CD45+c-kit+ precursors significantly peaks on days 5 to 7 in control bone marrow–derived eosinophil cultures supplemented only with IL-5, corresponding to IL-5–driven progenitor commitment to maturation in eosinophil lineage. After day 7, IL-5 receptor expression gradually decreases until eosinophils mature (Fig 1, E). In TNC-supplemented cultures, we detected significantly downregulated IL-5Rα expression during this time (Fig 1, E). Flow cytometry analysis showed that more than 70% of CD45+Lin− cells expressed IL-5Rα during the commitment phase in IL-5–supplemented culture. TNC addition resulted in nearly complete IL-5Rα expression loss during culture days 5 to 7 (see Fig E2 in this article's Online Repository at www.jacionline.org), suggesting this as the mechanism suppressing eosinophil progenitor maturation. TNC served as a reversible eosinophil maturation block, as its removal from cultures on day 6 (after the Il-5Rα suppression phase) completely rescued normal eosinophil maturation as evidenced by morphology (Fig 2, A). Flow cytometry confirmed the reversal to a mature phenotype, as all TNC withdrawal group eosinophils lost Sca-1 expression (Fig 2, A). Also, TNC withdrawal from culture doubled the final mature eosinophil yield (Fig 2, B). This is likely due to the initial eosinophil precursor expansion during the first week in TNC-enriched culture, the differentiation potential of which was fulfilled by IL-5 after TNC withdrawal. As such, temporary TNC deposition corresponding to a fluctuating provisional ECM environment may represent a mechanism by which tissues locally expand eosinophil progenitors and rapidly supply effector eosinophils during progressing repair or remodeling stages. Current eosinophil depletion strategies that target IL-5 (mepolizumab) or IL-5Rα (benralizumab) achieve only partial eosinophil depletion and 50% success in clinical trials.E14Saco T.V. Pepper A.N. Lockey R.F. Benralizumab for the treatment of asthma.Expert Rev Clin Immunol. 2017; 13: 405-413Crossref PubMed Scopus (17) Google Scholar, E15Patterson M.F. Borish L. Kennedy J.L. The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review.J Asthma Allergy. 2015; 8: 125-134PubMed Google Scholar Moreover, mepolizumab was found to reduce airway eosinophil numbers in asthma but not their functional phenotype.9Kelly E.A. Esnault S. Liu L.Y. Evans M.D. Johansson M.W. Mathur S. et al.Mepolizumab attenuates airway eosinophil numbers, but not their functional phenotype, in asthma.Am J Respir Crit Care Med. 2017; 196: 1385-1395Crossref PubMed Scopus (86) Google Scholar Provisional matrix components such as TNC may explain the only partial success of these therapies, which target cytokine drivers of eosinophil maturation but fail to address tissue factors driving eosinophil progenitors in situ. Finally, using an allergic airway inflammation model, we showed that allergen-challenged lungs of TNC-deficient (TNC−/−) mice lacked both CD45+c-kit+CD34+ common myeloid progenitors and CD45+Lin−Siglec-F+Sca-1+ eosinophil precursors compared with wild-type (WT) controls (Fig 2, C; see Fig E3 in this article's Online Repository at www.jacionline.org). To control for the potentially confounding recruitment of eosinophils and their progenitors from bone marrow during allergic inflammation, we cultured complete lung homogenates from WT and TNC−/− mice in the presence of IL-5 ex vivo. Remarkably, the untreated lung homogenates culture with IL-5 was sufficient to conservatively yield up to 20% mature eosinophils (out of CD45+ hematopoietic cells, measured by flow cytometry), implicating the significant recruitment-independent in situ hematopoietic potential of resting lung tissue. Eosinophil maturation was significantly accelerated in the ex vivo culture of TNC−/− lungs (Fig 2, D). Adding TNC to lung homogenates promoted CD45+Lin−Siglec-F+Sca-1+ cell expansion and significantly inhibited eosinophil maturation in WT and TNC−/− cultures (Fig 2, D), consistent with TNC's function as an eosinophil maturation block. Interestingly, eosinophil morphology was dramatically different in TNC−/− lung cultures with hypersegmented nuclei and vacuoles typical of airway eosinophils during allergic inflammation. Adding TNC “rescued” the wild-type eosinophil phenotype, with a ring-shaped nucleus and no vacuoles. This phenotype is reported for stromal, subepithelial eosinophils (where TNC is found in vivo), which may implicate TNC as a factor dictating the compartment-specific eosinophil phenotype in vivo. Collectively, our results illustrate the significant potential of the provisional ECM to support a hematopoietic niche environment and control eosinophil progenitor in situ expansion and maturation, which has significant implications for future strategies looking to limit tissue eosinophils in allergic diseases. All experiments were performed with 6- to 12-week-old female C57BL/6J mice (Jackson Labs, Bar Harbor, Me) and age-matched female TNC−/− mice (C57BL/6 N-TgH, from RIKEN, Saitama, Japan). The mice were sensitized by an intraperitoneal injection (200 μL) of ovalbumin (OVA) grade V 10 μg/alum or saline/alum on days 0 and 7 and then challenged intranasally on days 15 (Ch1), 17 (Ch2), and 19 (Ch3) with OVA grade VI (50 μg/50 μL saline) or saline alone. Tissues were harvested and processed for analysis at 24 hours after the last OVA challenge. All experiments were performed with 6- to 12-week-old female C57BL/6J mice (Jackson Labs) and age-matched female TNC−/− mice (C57BL/6 N-TgH, from RIKEN). Eosinophils were cultured following the established murine bone marrow culture protocol (see Dyer et alE8Dyer K.D. Moser J.M. Czapiga M. Siegel S.J. Percopo C.M. Rosenberg H.F. Functionally competent eosinophils differentiated ex vivo in high purity from normal mouse bone marrow.J Immunol. 2008; 181: 4004-4009Crossref PubMed Scopus (204) Google Scholar). The cytokine treatment timeline and stages of eosinophil development in this culture are illustrated in Fig 1, A. Samples underwent 3 different TNC treatments: nontreated (cytokines only, no TNC), TNC treatment (cytokines plus constitutively administered TNC), and TNC withdrawal (cytokines, TNC withdrawal from culture at day 7, further supplemented only with 10 ng/mL mIL-5). For TNC treatments, we used 25 μg/mL of MAPTrix TNC peptide corresponding to fibronectin type III (FN3) binding domain (MAPTrix motif: M-VAEIDGIEL) (Sigma, St Louis, Mo; 168314K; Kollodis Biosciences, North Augusta, SC). For ex vivo lung cultures, lungs were harvested in sterile conditions and cultured in SCF, FLT3, and IL-5 according to the protocol described in Fig 1, A. To preserve all lung tissue cellular interactions, structural cells were allowed to adhere and form a monolayer under the proliferating hematopoietic cells, which was maintained at all time points in the culture. Ex vivo culture of the lung tissue in IL-5 resulted in a significant in situ mature eosinophil yield and allowed us to control for confounding eosinophil progenitor recruitment from the bone marrow. Cells were harvested from plates and washed in 1× PBS in preparation for flow cytometry. Before antibody staining, cells were incubated in 500 μL 1× PBS with 0.25 μL Zombie Live/Dead dye (Biolegend, San Diego, Calif) in the dark at room temperature for 20 minutes followed by wash steps and incubation at 4°C for 10 minutes with 0.75 μL/50 μL murine FC Block (BD Biosciences, San Jose, Calif). Antibody cocktail was added directly to blocked samples and incubated for 30 minutes at 4°C. All centrifugation steps were carried out at 300g for 5 minutes in a swing bucket centrifuge. We used the following panel of antibodies and fluorescent dyes to characterize eosinophil cultures: (1) Zombie Live/Dead Fixable Viability Dye (Biolegend/Aqua/0.25 μL); (2) Lineage antibody mix (CD11b [clone M1/70], Ter119 [clone TER119], CD3 [clone 17A2], CD4 [clone RM4-5], CD8a [clone 53-6.7], CD19 [clone 6D5], Ly-6G/Ly-6C [Gr1] [clone RB6-8C5], B220 [clone RA3-6B2]) (Biolegend/PerCP-Cy5.5/0.3 μL each); (3) Ly-6A/E (Sca-1) (clone D7/Biolegend/PE-Cy7/0.5 μL); (4) CD127 (IL-7Rα) (clone A7R34/Biolegend/PE/0.4 μL); (5) CD117 (c-kit) (clone 2B8/Biolegend/PE Dazzle 594/0.4 μL); (6) CD125 (IL-5Rα) (clone T21/BD Biosciences/Alexa Fluor 488/0.5 μL); (7) CD45 (clone 30-F11/Biolegend/Alexa Fluor 700/0.5 μL); (8) Siglec-F (clone E50-2440/BD Biosciences/APC-Cy7/1 μL); (9) CD34 (clone MEC14.7/Biolegend/Alexa Fluor 647/1.25 μL); and (10) IL-33Ra (IL1RL1, ST2) (clone DIH9/Biolegend/Brilliant Violet 421/1.75 μL). Samples were fixed in 2% paraformaldehyde and kept in the dark at 4°C before acquisition. Samples were acquired on a BD LSRII flow cytometer (BD Biosciences). Bead compensation (OneComp; eBioscience, San Diego, Calif, and ArC; Molecular Probes beads, Eugene, Ore), gating, and data analysis were performed using FlowJo v.10 (TreeStar, Inc, Ashland, Ore). Only live, single, hematopoietic (CD45+) cells were used in analyses. Fluorescence Minus One controls were used to determine gate boundaries during analysis steps. Cells cytospun from bronchoalveolar lavages or ex vivo lung homogenates cultured in IL-5 were stained with initial fixation/staining in Wright Giemsa solution (EMD Millipore, Burlington, Mass) for 2 minutes, incubated in Eosin Xanthene dye for 3 minutes, and dipped twice in Hematoxylin/Blue/Azure (Electron Microscopy Science). Nuclear morphology and eosin granule staining were visualized at 40× on Olympus DSU microscope (Olympus, Tokyo, Japan). Mature eosinophil counts were performed in a blinded fashion on 10 different 40× fields per slide. Eosinophil counts were normalized to total cell counts. ANOVA followed by Tukey post hoc pairwise comparisons was used to assess differences between groups. Kinetics data were analyzed by repeated-measures ANOVA (SYSTAT 11, Systat Software, Inc, San Jose, Calif). Alpha level used for significance cutoffs was 0.05. All data are presented as the means ± SEM.Fig E2Expression of IL-5Rα on CD45+Siglec-F+ eosinophil progenitors at day 6 in bone marrow culture. FMO, Fluorescence Minus One.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Quantification of flow cytometry data shown in Fig 2, C. *P < .05. ****P < .0001.View Large Image Figure ViewerDownload Hi-res image Download (PPT)" @default.
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• W2799994211 title "Matrix protein tenascin-C expands and reversibly blocks maturation of murine eosinophil progenitors" @default.
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