Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The motheaten mouse, characterized by complex autoimmune and inflammatory diseases, arises from mutations in Ptpn6, encoding protein-tyrosine phosphatase Shp1.
• Shp1's broad regulatory roles across various hematopoietic cells obscure the precise mechanisms driving the motheaten phenotype.
• Understanding Shp1's cell-specific functions is crucial for elucidating the pathogenesis of autoimmune and inflammatory conditions.

Purpose of the Study:

• To investigate the specific roles of Shp1 in innate immune cells in the context of the motheaten phenotype.
• To differentiate the cellular contributions of neutrophils and dendritic cells to autoimmunity and inflammation.
• To identify the molecular signaling pathways affected by Shp1 deficiency in distinct immune cell populations.

Main Methods:

• Utilized floxed Ptpn6 mice to enable conditional deletion of the Ptpn6 gene in specific cell types.
• Generated mouse models with Ptpn6 deletion specifically in neutrophils or dendritic cells.
• Performed genetic and biochemical analyses to examine signaling pathways, including integrin and MyD88-dependent pathways.

Main Results:

• Neutrophil-specific Ptpn6 deletion led to cutaneous inflammation, modeling human neutrophilic dermatoses, but did not cause autoimmunity.
• Dendritic cell-specific Ptpn6 deletion resulted in severe autoimmunity without inflammation.
• Inflammation was linked to enhanced neutrophil integrin signaling via Src-family and Syk kinases; autoimmunity stemmed from exaggerated MyD88-dependent signaling in dendritic cells.

Conclusions:

• Shp1 regulates distinct signaling pathways in neutrophils and dendritic cells that differentially contribute to the motheaten phenotype.
• Neutrophil Ptpn6 deficiency drives inflammation through integrin signaling, while dendritic cell Ptpn6 deficiency promotes autoimmunity via MyD88 signaling.
• The complex autoimmune and inflammatory disease in motheaten mice arises from the combined disruption of Shp1-regulated pathways in different innate immune cell types.