Abstract
Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb−/− mice were explored on bone marrow-derived macrophages using phosphoproteomic analysis. As such, LPS tolerance decreased several phosphoproteins in the FcGRIIb−/− macrophage, including protein kinase C-β type II (PRKCB), which was associated with phagocytosis function. Overexpression of PRKCB attenuated LPS tolerance in RAW264.7 cells, supporting the role of this gene in LPS tolerance. In parallel, LPS tolerance in macrophages and in mice was attenuated by phorbol 12-myristate 13-acetate (PMA) administration. This treatment induced several protein kinase C families, including PRKCB. However, PMA attenuated the severity of mice with cecal ligation and puncture on LPS tolerance preconditioning in FcGRIIb−/− but not in wild-type cells. The significant reduction of PRKCB in the FcGRIIb−/− macrophage over wild-type cell possibly induced the more severe LPS-exhaustion and increased the infection susceptibility in FcGRIIb−/− mice. PMA induced PRKCB, improved LPS-tolerance, and attenuated sepsis severity, predominantly in FcGRIIb−/− mice. PRKCB enhancement might be a promising strategy to improve macrophage functions in lupus patients with LPS-tolerance from chronic infection.
Highlights
The Fc gamma receptor (FcGR) is a receptor for the Fc portion of immunoglobulin and FcGRIIb is the only inhibitory receptor within the FcGR family [1]
LPS tolerance is a helpful mechanism against LPS intoxication, with a decreased response to LPS exposure increasing mouse survival in an LPS injection model; in sepsis, LPS tolerance increases patient susceptibility to opportunistic infections and inhibits monocytes from the adequate production of inflammatory cytokines [7,8,9]
Because (i) FcGRIIb−/− macrophages are hyperresponsive following the first dose of LPS activation, but are markedly exhausted after the second dose, and (ii) the post-translational modification by phosphorylation is a common mechanism of rapid protein alteration and functional changes, we postulated that the phosphoproteomes of wild-type and FcGRIIb−/− cells will respond differently to LPS stimulation and performed phosphoproteomic analysis to test this hypothesis
Summary
The Fc gamma receptor (FcGR) is a receptor for the Fc portion of immunoglobulin and FcGRIIb is the only inhibitory receptor within the FcGR family [1]. LPS tolerance is a helpful mechanism against LPS intoxication, with a decreased response to LPS exposure (mainly through reduced cytokine production) increasing mouse survival in an LPS injection model; in sepsis, LPS tolerance increases patient susceptibility to opportunistic infections and inhibits monocytes from the adequate production of inflammatory cytokines [7,8,9]. These effects suggest a possible link between LPS tolerance and the immune exhaustion phase of sepsis. Because (i) FcGRIIb−/− macrophages (in comparison with wild-type cells) are hyperresponsive following the first dose of LPS activation, but are markedly exhausted after the second dose, and (ii) the post-translational modification by phosphorylation is a common mechanism of rapid protein alteration and functional changes, we postulated that the phosphoproteomes of wild-type and FcGRIIb−/− cells will respond differently to LPS stimulation and performed phosphoproteomic analysis to test this hypothesis
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