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PMID: 21880713 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid.

The Journal of biological chemistry ·Vol. 286 ·No. 43 ·2011-10-28 ·Pages 37358-67

Lin L, Bankaitis E, Heimbach L, Li N, Abrink M, Pejler G, An L, Diaz LA, Werb Z, Liu Z

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.

MeSH Terms
Animals Autoantigens/genetics,metabolism Basement Membrane/enzymology,pathology Cell Degranulation/drug effects,physiology Disease Models, Animal Enzyme Activation/drug effects,genetics Hemidesmosomes/enzymology,genetics,pathology Humans Immunoglobulin G/toxicity Mast Cells/enzymology,pathology Matrix Metalloproteinase 9/genetics,metabolism Mice Mice, Knockout Neutrophils/enzymology,pathology Non-Fibrillar Collagens/genetics,metabolism Pemphigoid, Bullous/chemically induced,enzymology,genetics,pathology Serine Endopeptidases/genetics,metabolism Skin/enzymology,pathology
Chemicals
Autoantigens Immunoglobulin G Non-Fibrillar Collagens collagen type XVII Serine Endopeptidases mast cell protease 4 Matrix Metalloproteinase 9
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Lin Lan
School of Life Science and Biotechnology, Dalian University of Technology, Dalian, 116024 Liaoning, China.
Bankaitis Eric
Heimbach Lisa
Li Ning
Abrink Magnus
Pejler Gunnar
An Lijia
Diaz Luis A
Werb Zena
Liu Zhi
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M111.272401
Published
2011-10-28
Epub
2011-00-31
Pages
37358-67
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3199483
Subset
IM
Grants
NIAID NIH HHS · R01 AI061430 · United States
NIAID NIH HHS · R01 AI040768 · United States
NIAMS NIH HHS · R37 AR032081 · United States
NIAMS NIH HHS · AR32599 · United States
NIAMS NIH HHS · AR053313 · United States
NCI NIH HHS · R01 CA057621 · United States
NIAMS NIH HHS · R01 AR032599 · United States
NIAMS NIH HHS · AR052109 · United States
NIAMS NIH HHS · AR32081 · United States
NIAID NIH HHS · AI61430 · United States
NIAID NIH HHS · R29 AI040768 · United States
NCI NIH HHS · CA057621 · United States
NIAMS NIH HHS · R01 AR032081 · United States
NIAID NIH HHS · AI40768 · United States
NIAMS NIH HHS · K01 AR052109 · United States
NIAMS NIH HHS · R03 AR053313 · United States
External Links
PubMed source DOI: 10.1074/jbc.M111.272401 PMC Full Text View journal details
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