Dual Targets for Mouse Mast Cell Protease-4 in Mediating Tissue Damage in Experimental Bullous Pemphigoid

Sammanfattning

Mouse mast cell protease-4 (mMCP-4) has been linked to autoimmune and inflammatory diseases, although the exact mechanisms underlying its role in these pathological conditions remain unclear. Here, we have found that mMCP-4 is critical in a mouse model of the autoimmune skin blistering disease bullous pemphigoid (BP). Mice lacking mMCP-4 were resistant to experimental BP. Complement activation, mast cell (MC) degranulation, and the early phase of neutrophil (PMN) recruitment occurred comparably in mMCP-4(-/-) and WT mice. However, without mMCP-4, activation of matrix metalloproteinase (MMP)-9 was impaired in cultured mMCP-4(-/-) MCs and in the skin of pathogenic IgG-injected mMCP-4(-/-) mice. MMP-9 activation was not fully restored by local reconstitution with WT or mMCP-4(-/-) PMNs. Local reconstitution with mMCP-4(-/-) MCs, but not with mMCP-4(-/-) MCs, restored blistering, MMP-9 activation, and PMN recruitment in mMCP-4(-/-) mice. mMCP-4 also degraded the hemidesmosomal transmembrane protein BP180 both in the skin and in vitro. These results demonstrate that mMCP-4 plays two different roles in the pathogenesis of experimental BP, by both activating MMP-9 and by cleaving BP180, leading to injury of the hemidesmosomes and extracellular matrix of the basement membrane zone.

Publicerad i

Journal of Biological Chemistry
2011, volym: 286, nummer: 43, sidor: 37358-37367
Utgivare: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

SLU författare

• Åbrink, Magnus

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

• Pejler, Gunnar

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Molekylärbiologi
Mikrobiologi
Biokemi

Publikationens identifierare

• DOI: https://doi.org/10.1074/jbc.M111.272401

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/59318