Advertisement

Molecular Medicine

, Volume 18, Issue 3, pp 486–496 | Cite as

The Receptor That Tames the Innate Immune Response

  • Michael Brines
  • Anthony Cerami
Review Article

Abstract

Tissue injury, hypoxia and significant metabolic stress activate innate immune responses driven by tumor necrosis factor (TNF)-α and other proinflammatory cytokines that typically increase damage surrounding a lesion. In a compensatory protective response, erythropoietin (EPO) is synthesized in surrounding tissues, which subsequently triggers antiinflammatory and antiapoptotic processes that delimit injury and promote repair. What we refer to as the sequelae of injury or disease are often the consequences of this intentionally discoordinated, primitive system that uses a “scorched earth” strategy to rid the invader at the expense of a serious lesion. The EPO-mediated tissue-protective system depends on receptor expression that is upregulated by inflammation and hypoxia in a distinctive temporal and spatial pattern. The tissue-protective receptor (TPR) is generally not expressed by normal tissues but becomes functional immediately after injury. In contrast to robust and early receptor expression within the immediate injury site, EPO production is delayed, transient and relatively weak. The functional EPO receptor that attenuates tissue injury is distinct from the hematopoietic receptor responsible for erythropoiesis. On the basis of current evidence, the TPR is composed of the β common receptor subunit (CD131) in combination with the same EPO receptor subunit that is involved in ery-thropoiesis. Additional receptors, including that for the vascular endothelial growth factor, also appear to be a component of the TPR in some tissues, for example, the endothelium. The discoordination of the EPO response system and its relative weakness provide a window of opportunity to intervene with the exogenous ligand. Recently, molecules were designed that preferentially activate only the TPR and thus avoid the potential adverse consequences of activating the hematopoietic receptor. On administration, these agents successfully substitute for a relative deficiency of EPO production in damaged tissues in multiple animal models of disease and may pave the way to effective treatment of a wide variety of insults that cause tissue injury, leading to profoundly expanded lesions and attendant, irreversible sequelae.

Notes

Acknowledgments

We thank Michael Yamin for his comments and suggestions about this manuscript.

References

  1. 1.
    Kedzierski L, Montgomery J, Curtis J, Handman E. (2004) Leucine-rich repeats in host-pathogen interactions. Arch. Immunol. Ther. Exp. (Warsz). 52:104–12.PubMedGoogle Scholar
  2. 2.
    Janssens S, Beyaert R. (2003) Role of Toll-like receptors in pathogen recognition. Clin. Microbiol. Rev. 16:637–46.CrossRefPubMedGoogle Scholar
  3. 3.
    Andersson U, Tracey KJ. (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29:139–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Dzik JM. (2010) The ancestry and cumulative evolution of immune reactions. Acta. Biochim. Pol. 57:443–66.PubMedGoogle Scholar
  5. 5.
    Huffaker A, Pearce G, Ryan CA. (2006) An endogenous peptide signal in Arabidopsis activates components of the innate immune response. Proc. Natl. Acad. Sci. U. S. A. 103:10098–103.CrossRefPubMedGoogle Scholar
  6. 6.
    Mann DL. (2011) The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ. Res. 108:1133–45.CrossRefPubMedGoogle Scholar
  7. 7.
    Bernaudin M, et al. (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19:643–51.CrossRefPubMedGoogle Scholar
  8. 8.
    Villa P, et al. (2003) Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J. Exp. Med. 198:971–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Nairz M, et al. (2011) Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-kappaB-inducible immune pathways. Immunity. 34:61–74.CrossRefPubMedGoogle Scholar
  10. 10.
    Siren AL, et al. (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. U. S. A. 98:4044–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Koh SH, Noh MY, Cho GW, Kim KS, Kim SH. (2009) Erythropoietin increases the motility of human bone marrow-multipotent stromal cells (hBM-MSCs) and enhances the production of neurotrophic factors from hBM-MSCs. Stem Cells Dev. 18:411–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Erbayraktar Z, et al. (2009) Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing. Mol. Med. 15:235–41.CrossRefPubMedGoogle Scholar
  13. 13.
    Kaiser K, et al. (2006) Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J. Infect. Dis 193:987–95.CrossRefPubMedGoogle Scholar
  14. 14.
    Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. (2008) Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar. J. 7:3.CrossRefPubMedGoogle Scholar
  15. 15.
    Rius J, et al. (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 453:807–11.CrossRefPubMedGoogle Scholar
  16. 16.
    Taylor CT. (2008) Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J. Physiol. 586:4055–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Jelkmann W. (2004) Molecular biology of erythropoietin. Intern. Med. 43:649–59.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang J, Ney P. (2007) EPOR signaling: 450 million years’ history. Blood. 110:2225–6.CrossRefGoogle Scholar
  19. 19.
    Ostrowski D, Ehrenreich H, Heinrich R. (2011) Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro. Neuroscience. 188:95–108.CrossRefPubMedGoogle Scholar
  20. 20.
    Koury MJ, Sawyer ST, Brandt SJ. (2002) New insights into erythropoiesis. Curr. Opin. Hematol. 9:93–100.CrossRefPubMedGoogle Scholar
  21. 21.
    Lacombe C, Mayeux P. (1999) The molecular biology of erythropoietin. Nephrol. Dial. Transplant. 14 (Suppl. 2):22–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Masuda S, et al. (1994) A novel site of erythropoietin production: oxygen-dependent production in cultured rat astrocytes. J. Biol. Chem. 269:19488–93.PubMedGoogle Scholar
  23. 23.
    Tsuda E, Kawanishi G, Ueda M, Masuda S, Sasaki R. (1990) The role of carbohydrate in recombinant human erythropoietin. Eur. J. Biochem. 188:405–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ. (2008) The erythropoietin receptor in normal and cancer tissues. Crit. Rev. Oncol. Hematol. 67:39–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Ebie AZ, Fleming KG. (2007) Dimerization of the erythropoietin receptor transmembrane domain in micelles. J. Mol. Biol. 366:517–24.CrossRefPubMedGoogle Scholar
  26. 26.
    Krzyzanski W, Wyska E. (2008) Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers. Naunyn Schmiedebergs Arch. Pharmacol. 377:637–45.CrossRefPubMedGoogle Scholar
  27. 27.
    Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 87:5978–82.CrossRefPubMedGoogle Scholar
  28. 28.
    Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T. (1993) Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res. 609:29–35.CrossRefPubMedGoogle Scholar
  29. 29.
    Westenfelder C, Biddle DL, Baranowski RL. (1999) Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int. 55:808–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Calvillo L, et al. (2003) Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc. Natl. Acad. Sci. U. S. A. 100:4802–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Masuda S, et al. (1993) Functional erythropoietin receptor of the cells with neural characteristics: comparison with receptor properties of erythroid cells. J. Biol. Chem. 268:11208–16.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Brines M, Cerami A. (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 264:405–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Leist M, et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 305:239–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Satake R, Kozutsumi H, Takeuchi M, Asano K. (1990) Chemical modification of erythropoietin: an increase in in vitro activity by guanidination. Biochim. Biophys. Acta. 1038:125–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Brines M, et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. U. S. A. 101:14907–12.CrossRefPubMedGoogle Scholar
  36. 36.
    Murphy JM, Young IG. (2006) IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitam. Horm. 74:1–30.CrossRefPubMedGoogle Scholar
  37. 37.
    Mirza S, Chen J, Murphy JM, Young IG. (2010) The role of interchain heterodisulfide formation in activation of the human common beta and mouse betaIL-3 receptors. J. Biol. Chem. 285: 24759–68.CrossRefPubMedGoogle Scholar
  38. 38.
    Stomski FC, et al. (1998) Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor het-erodimerization and activation of all three receptors. J. Biol. Chem. 273:1192–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Hanazono Y, Sasaki K, Nitta H, Yazaki Y, Hirai H. (1995) Erythropoietin induces tyrosine phosphorylation of the beta chain of the GM-CSF receptor. Biochem. Biophys. Res. Commun. 208:1060–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Jubinsky PT, Krijanovski OI, Nathan DG, Tavernier J, Sieff CA. (1997) The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood. 90:1867–73.PubMedGoogle Scholar
  41. 41.
    Nicola NA, et al. (1996) Functional inactivation in mice of the gene for the interleukin-3 (IL-3)-specific receptor beta-chain: implications for IL-3 function and the mechanism of receptor transmodulation in hematopoietic cells. Blood. 87:2665–74.PubMedGoogle Scholar
  42. 42.
    Scott CL, et al. (2000) Reassessment of interactions between hematopoietic receptors using common beta-chain and interleukin-3-specific receptor beta-chain-null cells: no evidence of functional interactions with receptors for erythropoietin, granulocyte colony-stimulating factor, or stem cell factor. Blood. 96:1588–90.PubMedGoogle Scholar
  43. 43.
    Loesch A, Tang H, Cotter MA, Cameron NE. (2010) Sciatic nerve of diabetic rat treated with epoetin delta: effects on C-fibers and blood vessels including pericytes. Angiology. 61:651–68.CrossRefPubMedGoogle Scholar
  44. 44.
    Colella P, et al. (2011) Non-erythropoietic erythropoietin derivatives protect from light-induced and genetic photoreceptor degeneration. Hum. Mol. Genet. 20:2251–62.CrossRefPubMedGoogle Scholar
  45. 45.
    Xu X, et al. (2009) Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery. 146:506–14.CrossRefPubMedGoogle Scholar
  46. 46.
    Kitamura H, et al. (2008) Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model. Nephrol. Dial. Transplant. 23:1521–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Joshi D, et al. (2010) Review of the role of erythropoietin in critical leg ischemia. Angiology. 61:541–50.CrossRefPubMedGoogle Scholar
  48. 48.
    Su KH, et al. (2011) β common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J. Cell. Physiol. 226:3330–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Carr PD, et al. (2001) Structure of the complete extracellular domain of the common beta subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration. Cell. 104: 291–300.CrossRefPubMedGoogle Scholar
  50. 50.
    Saulle E, et al. (2009) Colocalization of the VEGF-R2 and the common IL-3/GM-CSF receptor beta chain to lipid rafts leads to enhanced p38 activation. Br. J. Haematol. 145:399–411.CrossRefPubMedGoogle Scholar
  51. 51.
    Bagley CJ, Woodcock JM, Stomski FC, Lopez AF. (1997) The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors. Blood. 89:1471–82.PubMedGoogle Scholar
  52. 52.
    Lopez AF, et al. (2010) Molecular basis of cytokine receptor activation. IUBMB Life. 62:509–18.CrossRefPubMedGoogle Scholar
  53. 53.
    Um M, Gross AW, Lodish HF. (2007) A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. Cell Signal. 19:634–45.CrossRefPubMedGoogle Scholar
  54. 54.
    Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 126:3597–605.PubMedGoogle Scholar
  55. 55.
    Teng R, et al. (2011) Acute erythropoietin cardioprotection is mediated by endothelial response. Basic Res. Cardiol. 106:343–54.CrossRefPubMedGoogle Scholar
  56. 56.
    Colotta F, et al. (1993) Differential expression of the common beta and specific alpha chains of the receptors for GM-CSF, IL-3, and IL-5 in endothelial cells. Exp. Cell. Res. 206:311–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Xiong Y, et al. (2010) Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J. Neurotrauma. 27:205–15.CrossRefPubMedGoogle Scholar
  58. 58.
    Swartjes M, et al. (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology. 115:1084–92.CrossRefPubMedGoogle Scholar
  59. 59.
    Allegra A, Buemi M, Corica F, Aloisi C, Frisina N. (1999) Erythropoietin administration induces an increase of serum levels of soluble E-selectin and soluble intercellular adhesion molecule 1. Nephron. 82:361–2.CrossRefPubMedGoogle Scholar
  60. 60.
    Heinisch BB, et al. (2011) The effect of erythropoietin on platelet and endothelial activation markers: a prospective trial in healthy volunteers. Platelets. 2011, Nov 18 [Epub ahead of print].Google Scholar
  61. 61.
    Montero M, et al. (2007) Comparison of neuro-protective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures. Exp. Neurol. 204:106–17.CrossRefPubMedGoogle Scholar
  62. 62.
    Brines M, et al. (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 105:10925–30.CrossRefPubMedGoogle Scholar
  63. 63.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 76:105–16.CrossRefPubMedGoogle Scholar
  64. 64.
    Erbayraktar S, et al. (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuro-protective activity in vivo. Proc. Natl. Acad. Sci. U. S. A. 100:6741–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Mori S, Sawada T, Okada T, Kubota K. (2008) Erythropoietin and its derivative protect the intestine from severe ischemia/reperfusion injury in the rat. Surgery. 143:556–65.CrossRefPubMedGoogle Scholar
  66. 66.
    Okada T, Sawada T, Kubota K. (2007) Asialoery-thropoietin has strong renoprotective effects against ischemia-reperfusion injury in a murine model. Transplantation. 84:504–10.CrossRefPubMedGoogle Scholar
  67. 67.
    Sautina L, et al. (2010) Induction of nitric oxide by erythropoietin is mediated by the β common receptor and requires interaction with VEGF receptor 2. Blood. 115:896–905.CrossRefPubMedGoogle Scholar
  68. 68.
    Marrero MB, Venema RC, Ma H, Ling BN, Eaton DC. (1998) Erythropoietin receptor-operated Ca2+ channels: activation by phospholipase C-gamma 1. Kidney Int. 53:1259–68.CrossRefPubMedGoogle Scholar
  69. 69.
    Ahmet I, et al. (2011) A small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage. Mol. Med. 17:194–200.CrossRefPubMedGoogle Scholar
  70. 70.
    Ueba H, et al. (2010) Cardioprotection by a non-erythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 107:14357–62.CrossRefPubMedGoogle Scholar
  71. 71.
    Fu ZQ, et al. (2010) Effect of carbamylated ery-thropoietin on major histocompatibility complex expression and neural differentiation of human neural stem cells. J. Neuroimmunol. 221:15–24.CrossRefPubMedGoogle Scholar
  72. 72.
    Patel NS, et al. (2011) A nonerythropoietic peptide that mimicks the 3D structure of erythropoietin reduces organ injury/dysfunction and inflammation in experimental hemorrhagic shock. Mol. Med. 17:883–92.CrossRefPubMedGoogle Scholar
  73. 73.
    Moon C, et al. (2006) Erythropoietin, modified to not stimulate red blood cell production, retains its cardioprotective properties. J. Pharmacol. Exp. Ther. 316:999–1005.CrossRefPubMedGoogle Scholar
  74. 74.
    Wang L, et al. (2007) The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J. Biol. Chem. 282:32462–70.CrossRefPubMedGoogle Scholar
  75. 75.
    Taoufik E, et al. (2008) TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Proc. Natl. Acad. Sci. U. S. A. 105:6185–90.CrossRefPubMedGoogle Scholar
  76. 76.
    Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP. (1998) Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J. Cereb. Blood Flow Metab. 18:1283–7.CrossRefPubMedGoogle Scholar
  77. 77.
    Wang L, et al. (2011) Tumor necrosis factor alpha primes cerebral endothelial cells for erythropoietin-induced angiogenesis. J. Cereb. Blood Flow Metab. 31:640–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Junk AK, et al. (2002) Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc. Natl. Acad. Sci. U. S. A. 99:10659–64.CrossRefPubMedGoogle Scholar
  79. 79.
    Kanellakis P, et al. (2010) Darbepoetin-mediated cardioprotection after myocardial infarction involves multiple mechanisms independent of erythropoietin receptor-common beta-chain heteroreceptor. Br. J. Pharmacol. 160:2085–96.CrossRefPubMedGoogle Scholar
  80. 80.
    Woodcock JM, et al. (1997) The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor exists as a preformed receptor complex that can be activated by GM-CSF, interleukin-3, or interleukin-5. Blood. 90:3005–17.PubMedGoogle Scholar
  81. 81.
    Brines ML, et al. (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. U. S. A. 97:10526–31.CrossRefPubMedGoogle Scholar
  82. 82.
    Xiong Y, et al. (2011) Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury. J. Neurosurg. 114:549–59.CrossRefPubMedGoogle Scholar
  83. 83.
    Miskowiak K, O’Sullivan U, Harmer CJ. (2007) Erythropoietin enhances hippocampal response during memory retrieval in humans. J. Neurosci. 27:2788–92.CrossRefPubMedGoogle Scholar
  84. 84.
    Leconte C, et al. (2011) Comparison of the effects of erythropoietin and its carbamylated derivative on behaviour and hippocampal neurogenesis in mice. Neuropharmacology. 60:354–64.CrossRefPubMedGoogle Scholar
  85. 85.
    Su KH, et al. (2011) AMP-activated protein kinase mediates erythropoietin-induced activation of endothelial nitric oxide synthase. J. Cell. Physiol. 2011, Oct 20 [Epub ahead of print].Google Scholar
  86. 86.
    Meads MB, Li ZW, Dalton WS. (2010) A novel TNF receptor-associated factor 6 binding domain mediates NF-kappa B signaling by the common cytokine receptor beta subunit. J. Immunol. 185:1606–15.CrossRefPubMedGoogle Scholar
  87. 87.
    Grasso G, et al. (2006) Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonery-thropoietic erythropoietin derivative. J. Neurosurg. Spine. 4:310–8.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.Araim Pharmaceuticals, Inc.OssiningUSA
  2. 2.Leiden University Medical CenterLeidenThe Netherlands

Personalised recommendations