Background and objectives CARD9 is a CARMA-like intracellular protein that is highly expressed in myeloid cells. We previously presented that CARD9 plays an important role in the development of experimental arthritis and autoimmune blistering skin disease in mice, likely by linking the Syk tyrosine kinase to chemokine production in innate immune cells. Here, we investigated whether CARD9 expression in neutrophils is required for the in vivo pathogenesis.
Materials and methods Neutrophil-specific CARD9 deletion was achieved by crossing MRP8 promoter-driven Cre recombinase transgenic (MRP8-Cre) animals with Card9flox/flox mice (MRP8-Cre Card9flox/flox animals). The efficacy and specificity of lineage-specific deletion was analysed by Western-blot on neutrophil and macrophage cell lysates. Experimental arthritis was induced by a single intraperitoneal injection of K/BxN serum and was assessed by clinical scoring, ankle thickness measurements and by testing articular function. Epidermolysis bullosa acquisita was triggered by anti-collagen type VII antibodies.
Results In contrast to the wild type animals, neutrophils of the MRP8-Cre CARD9flox/flox mice did not express CARD9, while their macrophages had normal levels of the protein. Neutrophil-specific CARD9 deletion caused a partial, but significant decrease in the clinical arthritis score, the ankle thickening and the articular dysfunction, which did not differ significantly from that seen in Card9–/– animals. A similar phenomenon was observed in connexion with the autoimmune blistering skin disease as MRP8-Cre Card9flox/flox animals showed a substantial but incomplete reduction in inflammation, which was indistinguishable from the Card9–/– phenotype.
Conclusions CARD9 expression in neutrophils plays an important role in the development and progression of autoimmune arthritis and autoimmune blistering skin disease in mice, likely by controlling gene expression in these myeloid cells.
This project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
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