title: Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid.
abstract: 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.
authors: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024 Liaoning, China.
authors: Lan
authors: L
authors: Lin
authors: Eric
authors: E
authors: Bankaitis
authors: Lisa
authors: L
authors: Heimbach
authors: Ning
authors: N
authors: Li
authors: Magnus
authors: M
authors: Abrink
authors: Gunnar
authors: G
authors: Pejler
authors: Lijia
authors: L
authors: An
authors: Luis A
authors: LA
authors: Diaz
authors: Zena
authors: Z
authors: Werb
authors: Zhi
authors: Z
authors: Liu
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D001485:Basement Membrane / Q000201:enzymology / Q000473:pathology; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D022002:Hemidesmosomes / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity; D008407:Mast Cells / Q000201:enzymology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000473:pathology; D024041:Non-Fibrillar Collagens / Q000235:genetics / Q000378:metabolism; D010391:Pemphigoid, Bullous / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000201:enzymology* / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D007074:Immunoglobulin G; D020780:Matrix Metalloproteinase 9; D024041:Non-Fibrillar Collagens; D012697:Serine Endopeptidases; D000097805:Collagen Type XVII; C066932:mast cell protease 4