Neutrophil, quo vadis?

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Mar 30, 2017 - These cells were first observed by Paul Ehrlich, who developed unique methodology to stain leukocytes in 1880 [1]. The first to see neutrophils ...
Epub ahead of print March 30, 2017 - doi:10.1189/jlb.3MR0117-015R

Review

Neutrophil, quo vadis? Jadwiga Jablonska*,1 and Zvi Granot†,2 *Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany; and †Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel RECEIVED JANUARY 14, 2017; REVISED FEBRUARY 16, 2017; ACCEPTED MARCH 13, 2017. DOI: 10.1189/jlb.3MR0117-015R

ABSTRACT

NEUTROPHIL DIVERSITY IN DISEASE

Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with very defined roles in inflammation and fighting infections. However, recent advances in neutrophil research challenge this limited view and demonstrate that neutrophils are highly versatile, play different roles in various pathologic scenarios, and are heterogeneous. With this, it is becoming clear that one term—“neutrophil”—is too general, and more precise nomenclature is urgently required. In this mini review, we discuss the knowns and unknowns in neutrophil terminology and highlight the critical questions that should be addressed for the establishment of clear neutrophil nomenclature. J. Leukoc. Biol. 102: 000–000; 2017.

Neutrophils were shown to promote tumor growth and metastatic progression through secretion of tumor-promoting cytokines, enhancement of tumor angiogenesis, modulation of the extracellular matrix, and support of tumor cell dissemination, priming of the premetastatic niche, and suppression of antitumor immune responses [3, 6, 7]. On the other hand, in some experimental settings, neutrophils were shown to limit tumor growth and metastatic progression through direct cytotoxicity [8–10], antibody-dependent cell-mediated cytotoxicity, and stimulation of adaptive anti-tumor immunity [11]. These conflicting reports stirred a heated debate regarding the overall contribution of neutrophils to disease progression. This debate has led us and others to question whether neutrophils are truly a homogenous population or whether there are distinct neutrophil subsets possessing distinct functional traits. Perhaps not unexpectedly, neutrophils in the context of cancer were found to consist of both tumor-promoting and tumor-inhibitory subpopulations [12]. The ratio between these populations varies, may change with tumor progression, and determines the overall impact of neutrophils [12]. The existence of neutrophil populations with conflicting contributions to cancer progression resembles the functional plasticity that other nonmalignant cells display in the context of cancer [13] and helps to resolve the controversy surrounding neutrophil function in cancer. Concomitantly, this understanding raises new questions regarding the extent of neutrophil diversity and the definition of unique neutrophil subsets in health, in cancer, and in other diseases. Indeed, neutrophil diversity in cancer is not an isolated phenomenon, and neutrophil subpopulations were also observed in other mouse models of disease, including infection [14], angiogenesis [15], and graft versus host disease [16]. Importantly, various neutrophil populations were identified in various human clinical conditions, including HIV-1 infection [17], sepsis [18], psoriasis [19], malaria [20], periodontal disease [21], lupus

DEFINITION OF NEUTROPHILS Neutrophils are the most abundant population of WBCs in the circulation that play a key role in the innate immune system responses. These cells were first observed by Paul Ehrlich, who developed unique methodology to stain leukocytes in 1880 [1]. The first to see neutrophils in the process of phagocytosis was Elie Metchnikoff in 1883 [2]. Metchnikoff noticed cells that were capable of phagocytosing foreign matter, which were smaller than macrophages, and termed them microphages. Microphages were later termed neutrophils based on their neutral staining in H&E staining. Since their discovery, neutrophils were considered to be a homogenous population of terminally differentiated phagocytic cells involved in inflammatory responses. These two functions—fighting infections and promoting inflammation—are still the first that come to mind when neutrophils are discussed. Indeed, in a healthy organism, these two functions are those most evidently displayed. However, in the past two decades, neutrophils were found to have additional properties in health and disease. In some cases, neutrophils were found to play very different or even conflicting roles, a phenomenon that is best exemplified in the context of cancer [3–5]. Abbreviations: G-MDSC = granulocytic myeloid-derived suppressor cell, HDN = high-density neutrophil, LDN = low-density neutrophil, MDSC = myeloid-derived suppressor cell, NDN = normal-density neutrophil

1. Correspondence: Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany. E-mail: jadwiga. [email protected] 2. Correspondence: Dept. of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel 91120. E-mail: zvikag@ekmd. huji.ac.il

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[22], and others. Interestingly, different neutrophil subsets were also identified in healthy pregnant women [23].

NEUTROPHIL POPULATIONS With the understanding that neutrophils are not a homogenous population of cells, attempts came to make clear distinctions among different subsets, in a similar fashion to the ever-growing number of T cell subsets. Intriguingly, whereas different T cell subsets may often be distinguished according to specific cell surface makers, in neutrophils, this seems to be far more difficult. To date, there is no clear marker that may be used to distinguish conclusively between neutrophil subsets. At best, neutrophil subpopulations may be distinguished according to their physical properties (i.e., buoyancy or density). Circulating neutrophils may be separated, using a density gradient, into normal neutrophils (i.e., so-called HDNs), which migrate in the granulocytic fraction, and LDNs, which migrate in the mononuclear fraction. Neutrophils may be found in the high-density granulocytic fraction in states of both health and disease, whereas LDNs are propagated in pathologic states. Accordingly, we support using the terminology NDNs to describe cells migrating in the granulocytic fraction rather than HDNs, which may imply the existence of neutrophils with density higher than normal. LDNs and NDN possess very different properties. An excellent review on neutrophil diversity by Scapini et al. [24] discusses this issue at length. The authors highlight both functional properties of LDN in various clinical scenarios and their immunotype. Whereas this review provides a detailed account of LDN properties, we are left with many open questions. First, as mentioned above, there is no clear immunotype that fits all LDNs, and they often share the same surface markers as NDNs [24]. Second, there is no clear functional property that is associated with LDNs in general. For example, LDNs may possess anti-inflammatory or proinflammatory properties [24]. Finally, LDNs are often heterogeneous, consisting of both immature and mature neutrophils, making it clear that neutrophil phenotyping is still lacking. A further complication arises from the fact that most of the studies phenotyping LDN versus NDN use neutrophils isolated from peripheral blood rather than the relevant tissue (i.e., tumor, site of infection/inflammation). Neutrophils, being highly responsive to environmental cues, most likely acquire additional/different functional properties as they enter the tissue. Again, several aspects of this may be well demonstrated in the context of cancer. For example, it is commonly agreed that tumorassociated neutrophil s possess tumor-promoting (N2) rather than tumor-inhibiting (N1) properties [25]. Still, it is not clear whether these neutrophils originate from NDNs (N1 phenotype) that have acquired an N2 phenotype upon entering the tumor or from LDNs that possess an N2 phenotype even before their recruitment to the tumor bed. Several studies suggest that the N1/N2 polarization is determined by environmental cues and that modulation of these cues may skew the balance toward the N1 or N2 phenotype. This is exemplified in the case of TGF-b, where intratumoral depletion of this molecule promotes an N1 phenotype and neutrophil mediated anti-tumor cytotoxicity [26]. Likewise, the lack of IFN-b was identified to be responsible for the protumor N2 bias of neutrophils. This could be reversed by the treatment with recombinant IFN-b [6, 27]. Of note, the study by 2

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Andzinski et al. [28] shows that NDN neutrophils from melanoma patients show anti- or pro-tumor bias, depending on type I IFN treatment, suggesting a significant flexibility in neutrophil phenotype depending on the chemokine milieu. Furthermore, on many occasions, the immunosuppressive properties attributed to LDNs were evaluated using peripheral LDNs (circulation or spleen), and therefore, it is not clear whether peripheral LDNs, which possess immunosuppressive properties, actually provide immune suppression in the primary tumor. To make things more complicated, the majority of the mice studies that established pro- and anti-tumor functions of neutrophils do not distinguish between NDN and LDN but characterize neutrophils from blood and tissue based on the surface staining and sorting procedures. Therefore, simple direct translation between density characteristics of neutrophils and their pro- or anti-tumor (N1/N2) potential is unfeasible at the moment. With the assumption that neutrophils are indeed heterogeneous, the overall contribution of neutrophils in a given scenario would be determined by the ratio between the different neutrophil subsets. Taken together, these difficulties hinder the attempts to unify the neutrophil nomenclature and the efforts to establish a clear correlation between neutrophil phenotype and function.

NEUTROPHILS VERSUS MDSC The regulation of adaptive immune responses by neutrophils is a growing scientific field, as these cells were shown both to support or inhibit T cell proliferation, depending on activation status [29–32]. Recently, much attention was given to a heterogeneous population of suppressive myeloid cells, which consists of early myeloid progenitors and immature myeloid cells (immature monocytes, granulocytes, and dendritic cells) at different stages of differentiation. These cells were called MDSCs, although direct evidence, which suggests that these cells are nothing but a heterogeneous population of immature myeloid cells with suppressive capacities, is still missing. Furthermore, even though the initial intent to introduce MDSC nomenclature was not to define a novel population of myeloid cells but to provide terminology that encompasses the function, origin, and heterogeneity of these cells [33], it stirred further controversies in the myeloid research field. Apparently, numerous recent studies that examine the immunomodulatory role of MDSCs were actually describing immunosuppressive neutrophils. In such studies, authors are often content with using phenotypical evaluation of surface CD11b and/or Ly6G expression, whereas missing, at least in part, the characterization of the suppressive activities of these cells [34–36]. Moreover, neutrophil-depletion procedures using anti-Gr1 or anti-Ly6G antibodies are repeatedly presented as MDSC-depleting therapy [37, 38]. As these molecules are general granulocyte markers and are used for standard neutrophil depletion, it makes such MDSC-depleting strategy controversial. Similar difficulties are seen when trying to discern human neutrophils from human G-MDSC. The Ly6G epitope is not expressed on human neutrophils, and instead, CD66b is often used to identify neutrophils. Unfortunately, CD66b expression is also shared by G-MDSC hindering the attempts to discern these two populations.

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Jablonska and Granot Neutrophil, quo vadis?

DISTINCT POPULATIONS OR CONTINUUM OF PHENOTYPES Another issue, to complicate neutrophil terminology further, is the possibility that rather than representing truly distinct populations, neutrophils exist on a continuum of phenotypes. Neutrophils express a wide variety of surface receptors that gives them the ability to respond quickly to various environmental cues. The plasticity and versatility of these cells, as a result of different microenvironmental cues, make them highly heterogeneous, as they can change their phenotype, depending on the activating stimulus. Good examples of this are the polarization of neutrophils by TGF-b [26] or IFN-b [6, 28] in the tumor microenvironment and the TGF-b-driven conversion of NDNs to LDNs [12]. As currently there is no available marker to distinguish distinct neutrophil subsets in cancer, the possibility— that rather than representing true unique subsets, neutrophils exist on a continuum of phenotypes that can be skewed by environmental cues—remains valid [3].

CONCLUDING REMARKS Collectively, the observations made over the past two decades give a fresh look at neutrophils, a population of cells traditionally considered to be terminally differentiated with limited diversity and plasticity. The notion that neutrophils may consist of distinct populations challenges us to pursue in-depth characterization of these populations toward the identification of distinct subsets. Our growing understanding of neutrophil functional diversity raises new questions in basic neutrophil biology: are all neutrophils created equal? Are there subsets more prone to be proinflammatory? Are there subsets prone to be immunosuppressive? Are there subsets that are only propagated in states of disease? How does neutrophil composition (true subsets or skewed continuum) affect disease progression? Answering these questions is a major undertaking, as it requires both width (i.e., different pathologic scenarios and different tissues) and depth (i.e., analyses at the single-cell level). It is clear that although neutrophil subsets can be separated to NDNs and LDNs, according to physical properties, as discussed above, this is simply insufficient.

AUTHORSHIP J.J. and Z.G. wrote the manuscript and contributed equally.

ACKNOWLEDGMENTS J.J. was supported by German Research Council (DFG), Grant Number JA 2461/2-1 and Deutsche Krebshilfe, Grant Number 111647. Z.G. was supported by grants from the I-CORE Gene Regulation in Complex Human Disease, Center no. 41/11, the Israel Science Foundation (ISF), the Israel Cancer Research Foundation (RCDA) and the Israel Cancer Association.

DISCLOSURES

The authors declare no conflicts of interest.

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REFERENCES

1. Ehrlich, P. (1880) Methodologische beitrage zur physiologie und pathologie der verschisdenen formen der leukocyten. Z. Klin. Med. 1, 553–558. 2. Metchnikoff, E. 1883. Lectures on the Comparative Pathology of Inflammation. Kegan Paul, Trench, Trubner & Co. Ltd, London. 3. Granot, Z., Jablonska, J. (2015) Distinct functions of neutrophil in cancer and its regulation. Mediators Inflamm. 2015, 701067. 4. Piccard, H., Muschel, R. J., Opdenakker, G. (2012) On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit. Rev. Oncol. Hematol. 82, 296–309. 5. Sionov, R. V., Fridlender, Z. G., Granot, Z. (2015) The multifaceted roles neutrophils Play in the tumor microenvironment. Cancer Microenviron. 8, 125–158. 6. Jablonska, J., Leschner, S., Westphal, K., Lienenklaus, S., Weiss, S. (2010) Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J. Clin. Invest. 120, 1151–1164. 7. Wu, C. F., Andzinski, L., Kasnitz, N., Kr¨oger, A., Klawonn, F., Lienenklaus, S., Weiss, S., Jablonska, J. (2015) The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int. J. Cancer 137, 837–847. 8. Finisguerra, V., Di Conza, G., Di Matteo, M., Serneels, J., Costa, S., Thompson, A. A., Wauters, E., Walmsley, S., Prenen, H., Granot, Z., Casazza, A., Mazzone, M. (2015) MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353. 9. Granot, Z., Henke, E., Comen, E. A., King, T. A., Norton, L., Benezra, R. (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314. 10. L´opez-Lago, M. A., Posner, S., Thodima, V. J., Molina, A. M., Motzer, R. J., Chaganti, R. S. (2013) Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene 32, 1752–1760. 11. Van Egmond, M., Bakema, J. E. (2013) Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 23, 190–199. 12. Sagiv, J. Y., Michaeli, J., Assi, S., Mishalian, I., Kisos, H., Levy, L., Damti, P., Lumbroso, D., Polyansky, L., Sionov, R. V., Ariel, A., Hovav, A. H., Henke, E., Fridlender, Z. G., Granot, Z. (2015) Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Reports 10, 562–573. 13. Granot, Z., Fridlender, Z. G. (2015) Plasticity beyond cancer cells and the “immunosuppressive switch”. Cancer Res. 75, 4441–4445. 14. Tsuda, Y., Takahashi, H., Kobayashi, M., Hanafusa, T., Herndon, D. N., Suzuki, F. (2004) Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus. Immunity 21, 215–226. 15. Massena, S., Christoffersson, G., V˚agesj¨o, E., Seignez, C., Gustafsson, K., Binet, F., Herrera Hidalgo, C., Giraud, A., Lomei, J., Westr¨om, S., Shibuya, M., Claesson-Welsh, L., Gerwins, P., Welsh, M., Kreuger, J., Phillipson, M. (2015) Identification and characterization of VEGF-Aresponsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 126, 2016–2026. 16. Perobelli, S. M., Mercadante, A. C., Galvani, R. G., Gonçalves-Silva, T., Alves, A. P., Pereira-Neves, A., Benchimol, M., No´ brega, A., Bonomo, A. (2016) G-CSF-induced suppressor IL-10+ neutrophils promote regulatory T cells that inhibit graft-versus-host disease in a long-lasting and specific way. J. Immunol. 197, 3725–3734. 17. Cloke, T., Munder, M., Taylor, G., M¨uller, I., Kropf, P. (2012) Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection. PLoS One 7, e48939. 18. Darcy, C. J., Minigo, G., Piera, K. A., Davis, J. S., McNeil, Y. R., Chen, Y., Volkheimer, A. D., Weinberg, J. B., Anstey, N. M., Woodberry, T. (2014) Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit. Care 18, R163. 19. Lin, A. M., Rubin, C. J., Khandpur, R., Wang, J. Y., Riblett, M., Yalavarthi, S., Villanueva, E. C., Shah, P., Kaplan, M. J., Bruce, A. T. (2011) Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J. Immunol. 187, 490–500. 20. Rocha, B. C., Marques, P. E., Leoratti, F. M., Junqueira, C., Pereira, D. B., Antonelli, L. R., Menezes, G. B., Golenbock, D. T., Gazzinelli, R. T. (2015) Type I interferon transcriptional signature in neutrophils and low-density granulocytes are associated with tissue damage in malaria. Cell Reports 13, 2829–2841. 21. Fine, N., Hassanpour, S., Borenstein, A., Sima, C., Oveisi, M., Scholey, J., Cherney, D., Glogauer, M. (2016) Distinct oral neutrophil subsets define health and periodontal disease states. J. Dent. Res. 95, 931–938. 22. Lood, C., Blanco, L. P., Purmalek, M. M., Carmona-Rivera, C., De Ravin, S. S., Smith, C. K., Malech, H. L., Ledbetter, J. A., Elkon, K. B., Kaplan, M. J. (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153.

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23. Ssemaganda, A., Kindinger, L., Bergin, P., Nielsen, L., Mpendo, J., Ssetaala, A., Kiwanuka, N., Munder, M., Teoh, T. G., Kropf, P., Mu¨ ller, I. (2014) Characterization of neutrophil subsets in healthy human pregnancies. PLoS One 9, e85696. 24. Scapini, P., Marini, O., Tecchio, C., Cassatella, M. A. (2016) Human neutrophils in the saga of cellular heterogeneity: insights and open questions. Immunol. Rev. 273, 48–60. 25. Powell, D. R., Huttenlocher, A. (2016) Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52. 26. Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen, G. S., Albelda, S. M. (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194. 27. Andzinski, L., Wu, C. F., Lienenklaus, S., Kr¨oger, A., Weiss, S., Jablonska, J. (2015) Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN-b. Int. J. Cancer 136, 572–583. 28. Andzinski, L., Kasnitz, N., Stahnke, S., Wu, C. F., Gereke, M., von K¨ockritz-Blickwede, M., Schilling, B., Brandau, S., Weiss, S., Jablonska, J. (2016) Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int. J. Cancer 138, 1982–1993. 29. Eruslanov, E. B., Bhojnagarwala, P. S., Quatromoni, J. G., Stephen, T. L., Ranganathan, A., Deshpande, C., Akimova, T., Vachani, A., Litzky, L., Hancock, W. W., Conejo-Garcia, J. R., Feldman, M., Albelda, S. M., Singhal, S. (2014) Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J. Clin. Invest. 124, 5466–5480. 30. Mishalian, I., Bayuh, R., Eruslanov, E., Michaeli, J., Levy, L., Zolotarov, L., Singhal, S., Albelda, S. M., Granot, Z., Fridlender, Z. G. (2014) Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17–a new mechanism of impaired antitumor immunity. Int. J. Cancer 135, 1178–1186. 31. Tillack, K., Breiden, P., Martin, R., Sospedra, M. (2012) T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J. Immunol. 188, 3150–3159.

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32. Thewissen, M., Damoiseaux, J., van de Gaar, J., Tervaert, J. W. (2011) Neutrophils and T cells: bidirectional effects and functional interferences. Mol. Immunol. 48, 2094–2101. 33. Bronte, V., Brandau, S., Chen, S. H., Colombo, M. P., Frey, A. B., Greten, T. F., Mandruzzato, S., Murray, P. J., Ochoa, A., Ostrand-Rosenberg, S., Rodriguez, P. C., Sica, A., Umansky, V., Vonderheide, R. H., Gabrilovich, D. I. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150. 34. Finke, J., Ko, J., Rini, B., Rayman, P., Ireland, J., Cohen, P. (2011) MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int. Immunopharmacol. 11, 856–861. 35. Ku, A. W., Muhitch, J. B., Powers, C. A., Diehl, M., Kim, M., Fisher, D. T., Sharda, A. P., Clements, V. K., O’Loughlin, K., Minderman, H., Messmer, M. N., Ma, J., Skitzki, J. J., Steeber, D. A., Walcheck, B., OstrandRosenberg, S., Abrams, S. I., Evans, S. S. (2016) Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes. eLife 5, 5. 36. Shi, G., Wang, H., Zhuang, X. (2016) Myeloid-derived suppressor cells enhance the expression of melanoma-associated antigen A4 in a Lewis lung cancer murine model. Oncol. Lett. 11, 809–816. 37. Zhang, H., Wang, S., Huang, Y., Wang, H., Zhao, J., Gaskin, F., Yang, N., Fu, S. M. (2015) Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin. Immunol. 157, 175–186. 38. Srivastava, M. K., Zhu, L., Harris-White, M., Kar, U. K., Huang, M., Johnson, M. F., Lee, J. M., Elashoff, D., Strieter, R., Dubinett, S., Sharma, S. (2012) Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS One 7, e40677. KEY WORDS: normal density neutrophils low density neutrophils neutrophil subsets •

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Neutrophil, quo vadis? Jadwiga Jablonska and Zvi Granot J Leukoc Biol published online March 30, 2017 Access the most recent version at doi:10.1189/jlb.3MR0117-015R

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