Malin C Erlandsson1, Sofia Töyrä Silfverswärd1, Mitra Nadali2, Minna Turkkila1, Mattias N D Svensson1, Ing-Marie Jonsson1, Karin M E Andersson1, Maria I Bokarewa3. 1. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden. 2. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 12, 41346 Gothenburg, Sweden. 3. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden; Rheumatology Clinic, Sahlgrenska University Hospital, Gröna Stråket 12, 41346 Gothenburg, Sweden. Electronic address: maria.bokarewa@rheuma.gu.se.
Abstract
BACKGROUND: Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia. AIM: In the present study, we assess if disruption of IGF-1R signalling resolves arthritis. MATERIAL AND METHODS: Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates. RESULTS: In RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels. CONCLUSION: IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.
BACKGROUND: Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia. AIM: In the present study, we assess if disruption of IGF-1R signalling resolves arthritis. MATERIAL AND METHODS: Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RApatients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates. RESULTS: In RApatients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels. CONCLUSION:IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.
Authors: Melanie R Shapiro; Timothy P Foster; Daniel J Perry; Ron G Rosenfeld; Andrew Dauber; James A McNichols; Andrew Muir; Vivian Hwa; Todd M Brusko; Laura M Jacobsen Journal: Horm Res Paediatr Date: 2020-10-28 Impact factor: 2.852
Authors: Mitra Nadali; Rille Pullerits; Karin M E Andersson; Sofia Töyrä Silfverswärd; Malin C Erlandsson; Maria I Bokarewa Journal: Int J Mol Sci Date: 2017-11-13 Impact factor: 5.923
Authors: Karin M E Andersson; Caroline Wasén; Lina Juzokaite; Lovisa Leifsdottir; Malin C Erlandsson; Sofia T Silfverswärd; Anna Stokowska; Marcela Pekna; Milos Pekny; Kjell Olmarker; Rolf A Heckemann; Marie Kalm; Maria I Bokarewa Journal: Proc Natl Acad Sci U S A Date: 2018-12-03 Impact factor: 11.205
Authors: Malin C Erlandsson; Lovisa Lyngfelt; N David Åberg; Caroline Wasén; Rachelle A Espino; Sofia Töyrä Silfverswärd; Mitra Nadali; Katharina Jood; Karin M E Andersson; Rille Pullerits; Maria I Bokarewa Journal: BMC Med Date: 2019-07-22 Impact factor: 8.775
Authors: Philipp S Fuchs; Jonas Lötscher; Caroline M Berkemeier; Julia R Hirsiger; Adhideb Ghosh; Quan-Zhen Li; Nikolaus Deigendesch; Emanuel Christ; Alexander A Navarini; Mike Recher; Thomas Daikeler; Ingmar A F M Heijnen; Christoph T Berger Journal: Front Immunol Date: 2020-12-21 Impact factor: 7.561