Journal
LUPUS
Volume 29, Issue 10, Pages 1248-1262Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/0961203320941106
Keywords
FcgRIIb-deficient mice; systemic lupus erythematosus; endotoxin; (1 -> 3)-beta-D-glucan; gut leakage; spleen tyrosine kinase
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Funding
- Thailand Government Fund [RSA6080023]
- Thailand Government Fund 2016 to 2018
- Ratchadapisek Sompoch Endowment Fund Chulalongkorn University [760001-HR]
- International Research Network (IRN) The Thailand Research Fund [IRN59W0004]
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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)-beta-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 activatingFcgRs,NF-kappa BandSyk, together with supernatant TNF-alpha 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-alpha 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.
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