title: Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice.
abstract: The motheaten mouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations in Ptpn6, which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause the motheaten phenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in the motheaten mouse has remained unclear. By using floxed Ptpn6 mice, we dissected the contribution of innate immune cells to the motheaten phenotype. Ptpn6 deletion 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 cause motheaten disease.
authors.affiliation: Department of Laboratory Medicine and the Program in Immunology, University of California, San Francisco 94143, USA.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Abram
authors.forename: Gray L
authors.initials: GL
authors.lastname: Roberge
authors.forename: Lily I
authors.initials: LI
authors.lastname: Pao
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D020405:Dermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; D040501:Calgranulin A; D047908:Intracellular Signaling Peptides and Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C086145:S100a8 protein, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse