Targeting kallikrein 6-proteolysis attenuates CNS inflammatory disease

被引:85
作者
Blaber, SI
Ciric, B
Christophi, GP
Bernett, MJ
Blaber, M
Rodriguez, M
Scarisbrick, IA
机构
[1] Florida State Univ, Dept Chem & Biochem, Inst Mol Biophys, Tallahassee, FL 32306 USA
[2] Mayo Clin & Mayo Grad Sch Med, Program Mol Neurosci, Rochester, MN 55905 USA
[3] Mayo Clin & Mayo Grad Sch Med, Dept Immunol, Rochester, MN 55905 USA
[4] Mayo Clin & Mayo Grad Sch Med, Dept Neurol, Rochester, MN 55905 USA
[5] Mayo Clin & Mayo Grad Sch Med, Dept Phys Med & Rehabil, Rochester, MN 55905 USA
关键词
experimental autoimmune encephalomyelitis; myelin; inflammation; injury; enzyme;
D O I
10.1096/fj.03-1212fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Kallikrein 6 (K6, MSP) is a newly identified member of the Kallikrein family of serine proteases that is preferentially expressed in the adult central nervous system (CNS). We have previously demonstrated that K6 is abundantly expressed by inflammatory cells at sites of CNS inflammation and demyelination in animal models of multiple sclerosis (MS) and in human MS lesions. To test the hypothesis that this novel enzyme is a mediator of pathogenesis in CNS inflammatory disease, we have evaluated whether autonomously generated K6 antibodies alter the clinicopathological course of disease in murine proteolipid protein139-151-induced experimental autoimmune encephalomyelitis (PLP139-151 EAE). We demonstrate that immunization of mice with recombinant K6 generates antibodies that block K6 enzymatic activity in vitro, including the breakdown of myelin basic protein (MBP), and that K6-immunized mice exhibit significantly delayed onset and severity of clinical deficits. Reduced clinical deficits were reflected in significantly less spinal cord pathology and meningeal inflammation and in reduced Th1 cellular responses in vivo and in vitro. These data demonstrate for the first time that K6 participates in enzymatic cascades mediating CNS inflammatory disease and that this unique enzyme may represent a novel therapeutic target for the treatment of progressive inflammatory disorders, including MS.
引用
收藏
页码:920 / +
页数:25
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