Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation.

Autor: Norin U; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. Ulrika_norin@hotmail.com., Rintisch C; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; Medical Inflammation Research, Lund University, Lund, Sweden.; Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany., Meng L; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; The Second affiliated hospital to Xi'an Jiaotong University and the Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061, Xi'an, Shaanxi, China., Forster F; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Ekman D; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Stockholm, Sweden., Tuncel J; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Klocke K; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Bäcklund J; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Yang M; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Bonner MY; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Lahore GF; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., James J; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Shchetynsky K; Rheumatology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden., Bergquist M; Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden., Gjertsson I; Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Hubner N; Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.; Charité-Universitätsmedizin Berlin, Berlin, Germany., Bäckdahl L; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Holmdahl R; Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. rikard.holmdahl@ki.se.; The Second affiliated hospital to Xi'an Jiaotong University and the Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061, Xi'an, Shaanxi, China. rikard.holmdahl@ki.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 27; Vol. 12 (1), pp. 610. Date of Electronic Publication: 2021 Jan 27.
DOI: 10.1038/s41467-020-20586-2
Abstrakt: The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.
Databáze: MEDLINE