Distinct Roles for Neutrophils and Dendritic Cells in Inflammation and Autoimmunity inmotheatenMice

Themotheatenmouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations inPtpn6,which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause themotheatenphenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell ty...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2013-03, Vol.38 (3), p.489
Main Authors: Abram, Clare L, Roberge, Gray L, Pao, Lily I, Neel, Benjamin G, Lowell, Clifford A
Format: Article
Language:English
Subjects:
Bone marrow
Chemokines
Disease
Flow cytometry
Genotype & phenotype
Kinases
Laboratories
Mutation
Pathogenesis
Proteins
Studies
Survival analysis
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Summary:Themotheatenmouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations inPtpn6,which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause themotheatenphenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in themotheatenmouse has remained unclear. By using floxedPtpn6mice, we dissected the contribution of innate immune cells to themotheatenphenotype.Ptpn6deletion in neutrophils resulted in cutaneous inflammation, but not autoimmunity, providing an animal model of human neutrophilic dermatoses. By contrast, dendritic cell deletion caused severe autoimmunity, without inflammation. Genetic and biochemical analysis showed that inflammation was caused by enhanced neutrophil integrin signaling through Src-family and Syk kinases, whereas autoimmunity resulted from exaggerated MyD88-dependent signaling in dendritic cells. Our data demonstrate that disruption of distinct Shp1-regulated pathways in different cell types combine to causemotheatendisease.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2013.02.018