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.
Funding source: National Institutes of Health
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.
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©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Highlight: remodelling the KLK landscape down under
- HIGHLIGHT: 6TH INTERNATIONAL SYMPOSIUM ON KALLIKREINS AND KALLIKREIN-RELATED PEPTIDASES
- Kallikrein(K1)-kinin-kininase (ACE) and end-organ damage in ischemia and diabetes: therapeutic implications
- Mechanistic insight from murine models of Netherton syndrome
- Development of molecules stimulating the activity of KLK3 – an update
- Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors
- Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10
- Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer
- Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
- A viable mouse model for Netherton syndrome based on mosaic inactivation of the Spink5 gene
- Therapeutic modulation of tissue kallikrein expression
- In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B
- A computational analysis of the genetic and transcript diversity at the kallikrein locus
- Reviews
- Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome
- The power, pitfalls and potential of the nanodisc system for NMR-based studies
- Research Articles/Short Communications
- Cell Biology and Signaling
- Synergistic induction of cardiomyocyte differentiation from human bone marrow mesenchymal stem cells by interleukin 1β and 5-azacytidine