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Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis

  • Hyesook Yoon and Isobel A. Scarisbrick EMAIL logo
Published/Copyright: August 17, 2016

Abstract

Kallikrein-related peptidase 6 (Klk6) is elevated in the serum of multiple sclerosis (MS) patients and is hypothesized to participate in inflammatory and neuropathogenic aspects of the disease. To test this hypothesis, we investigated the impact of systemic administration of recombinant Klk6 on the development and progression of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). First, we determined that Klk6 expression is elevated in the spinal cord of mice with EAE at the peak of clinical disease and in immune cells upon priming with the disease-initiating peptide in vitro. Systemic administration of recombinant Klk6 to mice during the priming phase of disease resulted in an exacerbation of clinical symptoms, including earlier onset of disease and higher levels of spinal cord inflammation and pathology. Treatment of MOG35-55-primed immune cells with Klk6 in culture enhanced expression of pro-inflammatory cytokines, interferon-γ, tumor necrosis factor, and interleukin-17, while reducing anti-inflammatory cytokines interleukin-4 and interleukin-5. Together these findings provide evidence that elevations in systemic Klk6 can bias the immune system towards pro-inflammatory responses capable of exacerbating the development of neuroinflammation and paralytic neurological deficits. We suggest that Klk6 represents an important target for conditions in which pro-inflammatory responses play a critical role in disease development, including MS.

Award Identifier / Grant number: 5R01NS052741

Funding statement: Studies were supported by the National Institutes of Health 5R01NS052741, RG4958 from the National Multiple Sclerosis Society to I.A.S. The authors declare no competing financial interests.

Acknowledgments

Studies were supported by the National Institutes of Health 5R01NS052741, RG4958 from the National Multiple Sclerosis Society to I.A.S. The authors declare no competing financial interests.

References

Angelo, P.F., Lima, A.R., Alves, F.M., Blaber, S.I., Scarisbrick, I.A., Blaber, M., Juliano, L., and Juliano, M.A. (2006). Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects. J. Biol. Chem. 281, 3116–3126.10.1074/jbc.M510096200Search in Google Scholar

Bar-Or, A. (2016). Multiple sclerosis and related disorders: evolving pathophysiologic insights. Lancet Neurol. 15, 9–11.10.1016/S1474-4422(15)00342-7Search in Google Scholar

Bernett, M.J., Blaber, S.I., Scarisbrick, I.A., Dhanarajan, P., Thompson, S.M., and Blaber, M. (2002). Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem. 277, 24562–24570.10.1074/jbc.M202392200Search in Google Scholar PubMed

Blaber, S.I., Scarisbrick, I.A., Bernett, M.J., Dhanarajan, P., Seavy, M.A., Jin, Y., Schwartz, M.A., Rodriguez, M., and Blaber, M. (2002). Enzymatic properties of rat myelencephalon-specific protease. Biochemistry 41, 1165–1173.10.1021/bi015781aSearch in Google Scholar PubMed

Blaber, S.I., Ciric, B., Christophi, G.P., Bernett, M.J., Blaber, M., Rodriguez, M., and Scarisbrick, I.A. (2004). Targeting kallikrein 6-proteolysis attenuates CNS inflammatory disease. FASEB J. 19, 920–922.10.1096/fj.03-1212fjeSearch in Google Scholar PubMed

Burda, J.E., Radulovic, M., Yoon, H., and Scarisbrick, I.A. (2013). Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia 61, 1456–1470.10.1002/glia.22534Search in Google Scholar PubMed PubMed Central

Christophi, G.P., Isackson, P.J., Blaber, S.I., Blaber, M., Rodriguez, M., and Scarisbrick, I.A. (2004). Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease. J. Neurochem. 91, 1439–1449.10.1111/j.1471-4159.2004.02826.xSearch in Google Scholar PubMed

Ferber, I.A., Brocke, S., Taylor-Edwards, C., Ridgway, W., Dinisco, C., Steinman, L., Dalton, D., and Fathman, C.G. (1996). Mice with disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7.10.4049/jimmunol.156.1.5Search in Google Scholar

Guo, S., Skala, W., Magdolen, V., Brandstetter, H., and Goettig, P. (2014). Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity. Biol. Chem. 395, 959–976.10.1515/hsz-2014-0140Search in Google Scholar PubMed

Hebb, A.L., Bhan, V., Wishart, A.D., Moore, C.S., and Robertson, G.S. (2011). Human kallikrein 6 cerebrospinal levels are elevated in multiple sclerosis. Curr. Drug. Discov. Technol. 7, 137–140.10.2174/157016310793180611Search in Google Scholar PubMed

Komiyama, Y., Nakae, S., Matsuki, T., Nambu, A., Ishigame, H., Kakuta, S., Sudo, K., and Iwakura, Y. (2006). IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573.10.4049/jimmunol.177.1.566Search in Google Scholar PubMed

Kruglov, A.A., Lampropoulou, V., Fillatreau, S., and Nedospasov, S.A. (2011). Pathogenic and protective functions of TNF in neuroinflammation are defined by its expression in T lymphocytes and myeloid cells. J. Immunol. 187, 5660–5670.10.4049/jimmunol.1100663Search in Google Scholar PubMed

Kruisbeek, A.M., Shevach, E., and Thornton, A.M. (2004). Proliferative assays for T cell function. Curr. Protoc. Immunol. Chapter 3, Unit 3. 12.10.1002/0471142735.im0312s60Search in Google Scholar PubMed

Kuzmanov, U., Jiang, N., Smith, C.R., Soosaipillai, A., and Diamandis, E.P. (2009). Differential N-glycosylation of kallikrein 6 derived from ovarian cancer cells or the central nervous system. Mol. Cell Proteomics. 8, 791–798.10.1074/mcp.M800516-MCP200Search in Google Scholar PubMed PubMed Central

Liblau, R., Steinman, L., and Brocke, S. (1997). Experimental autoimmune encephalomyelitis in IL-4-deficient mice. Int. Immunol. 9, 799–803.10.1093/intimm/9.5.799Search in Google Scholar PubMed

McCarthy, D.P., Richards, M.H., and Miller, S.D. (2012). Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler’s virus-induced demyelinating disease. Methods Mol. Biol. 900, 381–401.10.1007/978-1-60761-720-4_19Search in Google Scholar PubMed PubMed Central

Miller, S.D., Karpus, W.J., and Davidson, T.S. (2010). Experimental autoimmune encephalomyelitis in the mouse. Curr. Protoc. Immunol. Chapter 15, Unit 15. 1.10.1002/0471142735.im1501s88Search in Google Scholar PubMed

Nylander, A. and Hafler, D.A. (2012). Multiple sclerosis. J. Clin. Invest. 122, 1180–1188.10.1172/JCI58649Search in Google Scholar PubMed PubMed Central

Oikonomopoulou, K., Hansen, K.K., Saifeddine, M., Tea, I., Blaber, M., Blaber, S.I., Scarisbrick, I., Andrade-Gordon, P., Cottrell, G. S., Bunnett, N.W., et al. (2006). Proteinase-activated receptors, targets for kallikrein signaling. J. Biol. Chem. 281, 32095–32112.10.1074/jbc.M513138200Search in Google Scholar PubMed

Panos, M., Christophi, G.P., Rodriguez, M., and Scarisbrick, I.A. (2014). Differential expression of multiple kallikreins in a viral model of multiple sclerosis points to unique roles in the innate and adaptive immune response. Biol. Chem. 395, 1063–1073.10.1515/hsz-2014-0141Search in Google Scholar PubMed PubMed Central

Radulovic, M., Yoon, H., Larson, N., Wu, J., Linbo, R., Burda, J.E., Diamandis, E.P., Blaber, S.I., Blaber, M., Fehlings, M.G., et al. (2013). Kallikrein cascades in traumatic spinal cord injury: in vitro evidence for roles in axonopathy and neuron degeneration. J. Neuropathol. Exp. Neurol. 72, 1072–1089.10.1097/NEN.0000000000000007Search in Google Scholar PubMed PubMed Central

Radulovic, M., Yoon, H., Wu, J., Mustafa, K., Fehlings, M.G., and Scarisbrick, I.A. (2015). Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury. Neurobiol. Dis. 83, 75–89.10.1016/j.nbd.2015.08.021Search in Google Scholar

Radulovic, M., Yoon, H., Wu, J., Mustafa, K., and Scarisbrick, I.A. (2016). Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury. Neurobiol. Dis. 93, 226–242.10.1016/j.nbd.2016.04.010Search in Google Scholar

Ransohoff, R.M., Hafler, D.A., and Lucchinetti, C.F. (2015). Multiple sclerosis-a quiet revolution. Nat. Rev. Neurol. 11, 134–142.10.1038/nrneurol.2015.14Search in Google Scholar

Scarisbrick, I.A. (2008). The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease. Curr. Top. Microbiol. Immunol. 318, 133–175.10.1007/978-3-540-73677-6_6Search in Google Scholar

Scarisbrick, I.A. and Blaber, M. (2012). Kallikrein-related peptidase 6. In: Handbook of Proteolytic Enzymes. A. J. Barrett and N.D. Rawlings, eds. (London, UK, Elsevier), pp. 2780–2786.10.1016/B978-0-12-382219-2.00612-8Search in Google Scholar

Scarisbrick, I.A., Towner, M.D., and Isackson, P.J. (1997). Nervous system specific expression of a novel serine protease: regulation in the adult rat spinal cord by excitotoxic injury. J. Neurosci. 17, 8156–8168.10.1523/JNEUROSCI.17-21-08156.1997Search in Google Scholar

Scarisbrick, I.A., Asakura, K., Blaber, S., Blaber, M., Isackson, P.J., Beito, T., Rodriguez, M., and Windebank, A.J. (2000). Preferential expression of myelencephalon specific protease by oligodendrocytes of the adult rat spinal cord white matter. Glia 30, 219–230.10.1002/(SICI)1098-1136(200005)30:3<219::AID-GLIA2>3.0.CO;2-2Search in Google Scholar

Scarisbrick, I.A., Isackson, P.J., Ciric, B., Windebank, A.J., and Rodriguez, M. (2001). MSP, a trypsin-like serine protease, is abundantly expressed in the human nervous system. J. Comp. Neurol. 431, 347–361.10.1002/1096-9861(20010312)431:3<347::AID-CNE1075>3.0.CO;2-KSearch in Google Scholar

Scarisbrick, I.A., Blaber, S.I., Lucchinetti, C.F., Genain, C.P., Blaber, M., and Rodriguez, M. (2002). Activity of a newly identified serine protease in CNS demyelination. Brain 125, 1283–1296.10.1093/brain/awf142Search in Google Scholar

Scarisbrick, I.A., Blaber, S.I., Tingling, J.T., Rodriguez, M., Blaber, M., and Christophi, G.P. (2006a). Potential scope of action of tissue kallikreins in CNS immune-mediated disease. J. Neuroimmunol. 178, 167–176.10.1016/j.jneuroim.2006.05.022Search in Google Scholar

Scarisbrick, I.A., Sabharwal, P., Cruz, H., Larsen, N., Vandell, A., Blaber, S.I., Ameenuddin, S., Papke, L.M., Fehlings, M.G., Reeves, R.K., et al. (2006b). Dynamic role of kallikrein 6 in traumatic spinal cord injury. Eur. J. Neuroscience 24, 1457–1469.10.1111/j.1460-9568.2006.05021.xSearch in Google Scholar

Scarisbrick, I.A., Linbo, R., Vandell, A.G., Keegan, M., Blaber, S.I., Blaber, M., Sneve, D., Lucchinetti, C. F., Rodriguez, M., and Diamandis, E.P. (2008). Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration. Biol. Chem. 389, 739–745.10.1515/BC.2008.085Search in Google Scholar PubMed PubMed Central

Scarisbrick, I.A., Epstein, B., Cloud, B.A., Yoon, H., Wu, J., Renner, D.N., Blaber, S.I., Blaber, M., Vandell, A. G., and Bryson, A.L. (2011). Functional role of kallikrein 6 in regulating immune cell survival. PLoS One 6, e18376; 18371–18311.10.1371/journal.pone.0018376Search in Google Scholar PubMed PubMed Central

Scarisbrick, I.A., Radulovic, M., Burda, J.E., Larson, N., Blaber, S.I., Giannini, C., Blaber, M., and Vandell, A.G. (2012a). Kallikrein 6 is a novel molecular trigger of reactive astrogliosis. Biol. Chem. 393, 355–367.10.1515/hsz-2011-0241Search in Google Scholar PubMed PubMed Central

Scarisbrick, I.A., Yoon, H., Panos, M., Larson, N., Blaber, S. I., Blaber, M., and Rodriguez, M. (2012b). Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis. Brain Pathol. 22, 709–722.10.1111/j.1750-3639.2012.00577.xSearch in Google Scholar PubMed PubMed Central

Schutzer, S.E., Angel, T.E., Liu, T., Schepmoes, A.A., Xie, F., Bergquist, J., Vecsei, L., Zadori, D., Camp, D.G., 2nd, Holland, B.K., et al. (2013). Gray matter is targeted in first-attack multiple sclerosis. PLoS One 8, e66117.10.1371/journal.pone.0066117Search in Google Scholar PubMed PubMed Central

Singh, V., van Pelt, E.D., Stoop, M.P., Stingl, C., Ketelslegers, I.A., Neuteboom, R.F., Catsman-Berrevoets, C.E., Luider, T.M., and Hintzen, R.Q. (2015). Gray matter-related proteins are associated with childhood-onset multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 2, e155.10.1212/NXI.0000000000000155Search in Google Scholar PubMed PubMed Central

Vandell, A.G., Larson, N., Laxmikanthan, G., Panos, M., Blaber, S.I., Blaber, M., and Scarisbrick, I.A. (2008). Protease activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J. Neurochem. 107, 855–870.10.1111/j.1471-4159.2008.05658.xSearch in Google Scholar PubMed PubMed Central

Yoon, H., Radulovic, M., Wu, J., Blaber, S.I., Blaber, M., Fehlings, M.G., and Scarisbrick, I.A. (2013). Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. J. Neurochem. 127, 283–298.10.1111/jnc.12293Search in Google Scholar PubMed PubMed Central

Yoon, H., Radulovic, M., Drucker, K. L., Wu, J., and Scarisbrick, I.A. (2015). The thrombin receptor is a critical extracellular switch controlling myelination. Glia 63, 846–859.10.1002/glia.22788Search in Google Scholar PubMed PubMed Central

Received: 2016-6-20
Accepted: 2016-8-10
Published Online: 2016-8-17
Published in Print: 2016-12-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: remodelling the KLK landscape down under
  4. HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
  5. Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
  6. Mechanistic insight from murine models of Netherton syndrome
  7. Development of molecules stimulating the activity of KLK3 – an update
  8. Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
  9. Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
  10. Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
  11. Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
  12. A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
  13. Therapeutic modulation of tissue kallikrein expression
  14. In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
  15. A computational analysis of the genetic and transcript diversity at the kallikrein locus
  16. Reviews
  17. Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
  18. The power, pitfalls and potential of the nanodisc system for NMR-based studies
  19. Research Articles/Short Communications
  20. Cell Biology and Signaling
  21. Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
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