| Autor: |
Aoun M; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., Cai X; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden.; Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Xu B; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., Lahore GF; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., Bonner MY; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., He Y; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., Bäckdahl L; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden., Holmdahl R; Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, 171 77 Stockholm, Sweden.; The Second Affiliated Hospital of Xi'an Jiaotong University, Xibei Hospital, Xi'an 710004, China. |
| Abstrakt: |
Animal models for complex diseases are needed to position and analyze the function of interacting genes. Previous positional cloning identified Ncf1 and Clec4b to be major regulators of arthritis models in rats. Here, we investigate epistasis between Ncf1 and Clec4b, two major regulators of arthritis in rats. We find that Clec4b and Ncf1 exert an additive effect on arthritis given by their joint ability to regulate neutrophils. Both genes are highly expressed in neutrophils, together regulating neutrophil availability and their capacity to generate reactive oxygen species. Using a glycan array, we identify key ligands of Clec4b and demonstrate that Clec4b-specific stimulation triggers neutrophils into oxidative burst. Our observations highlight Clec4b as an important regulator of neutrophils and demonstrate how epistatic interactions affect the susceptibility to, and severity of, autoimmune arthritis. |
