Publication: Syk inhibitor attenuates inflammation in lupus mice from FcgRIIb deficiency but not in pristane induction: the influence of lupus pathogenesis on the therapeutic effect
2
Issued Date
2020-09-01
Resource Type
ISSN
14770962
09612033
09612033
Other identifier(s)
2-s2.0-85088383196
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Lupus. Vol.29, No.10 (2020), 1248-1262
Suggested Citation
Jiraphorn Issara-Amphorn, Naraporn Somboonna, Prapaporn Pisitkun, Nattiya Hirankarn, Asada Leelahavanichkul Syk inhibitor attenuates inflammation in lupus mice from FcgRIIb deficiency but not in pristane induction: the influence of lupus pathogenesis on the therapeutic effect. Lupus. Vol.29, No.10 (2020), 1248-1262. doi:10.1177/0961203320941106 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/58015
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Syk inhibitor attenuates inflammation in lupus mice from FcgRIIb deficiency but not in pristane induction: the influence of lupus pathogenesis on the therapeutic effect
Other Contributor(s)
Abstract
© The Author(s) 2020. Macrophages are responsible for the recognition of pathogen molecules. The downstream signalling of the innate immune responses against pathogen molecules, lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), and the adaptive immune response to antibodies, Fc gamma receptor (FcgR), is spleen tyrosine kinase (Syk). Because pathogen molecules and antibodies could be presented in lupus, impact of Syk and macrophages in lupus is explored. FcgR-IIb deficient (FcgRIIb-/-) mice, a model of inhibitory signalling loss, at 40 weeks old, but not pristane mice (a chemical induction lupus model) demonstrated spontaneous elevation of LPS and BG in serum from gut translocation despite the similarity in faecal microbiome analysis. Syk abundance in FcgRIIb–/– mice was higher than in pristane mice, possibly due to several Syk activators (anti-dsDNA, LPS and BG), and Syk inhibitor–attenuated proteinuria and serum cytokines only in FcgRIIb–/– mice. In addition, LPS + BG enhanced the expression of activating FcgRs, NF-κB and Syk, together with supernatant TNF-α predominantly in FcgRIIb–/– compared to wild-type macrophages. The inhibitors against Dectin-1, Syk and nuclear factor kappa B, but not anti-Raf-1, reduced supernatant TNF-α in LPS+BG-activated macrophages, implying Syk-dependent signalling. The pathogen molecules enhanced activating-FcgRs, without inhibition, through Syk, a shared downstream innate and adaptive signalling, is responsible for the hyper-responsiveness in FcgRIIb–/– macrophages. In conclusion, Syk inhibitor attenuated inflammation in FcgRIIb–/– but not in pristane mice, implying the influence of a lupus genetic background in treatment modalities.