Abstract
In patients with active lupus, spontaneous endotoxemia and possibly tolerance to lipopolysaccharide (LPS) is a potentially adverse complication. Similarly, previous reports have demonstrated that FcGRIIb deficient mice (FcGRIIb-/-; a lupus mouse model) are susceptible to LPS tolerance-induced decreased cytokine responses that inadequate for the organismal control. Thus, understanding the relationship between FcGRIIb and LPS tolerance could improve the therapeutic strategy for lupus. LPS tolerance can be induced through sequential LPS stimulations in either cells or a model organism. In RAW264.7 (a mouse macrophage cell-line), sequential LPS stimulation induced the secretion of Lipocalin-2 (Lcn-2) despite reduced cytokine secretion and severe energy depletion, as measured by the extracellular flux analysis, typical of LPS tolerance. In contrast, treatment with recombinant Lcn-2 (rLcn-2) attenuated LPS tolerance, as shown by an increase in secreted cytokines and altered macrophage polarization toward M1 (increased iNOS and TNF-α) in RAW264.7 cells. These results suggest a role of Lcn-2 in LPS tolerance attenuation. In bone marrow derived macrophages, Lcn-2 level was similar in LPS tolerant FcGRIIb-/- and wild-type (WT) cells despite the increased LPS tolerance of FcGRIIb-/- cells, suggesting relatively low basal levels of Lcn-2 produced in FcGRIIb-/- cells. In addition, attenuation of LPS tolerance effectuated by granulocyte-monocyte colony stimulating factor (GM-CSF) reduced Lcn-2 in both cell types, implying an inverse correlation between Lcn-2 and the severity of LPS tolerance. Consequently, rLcn-2 improved LPS tolerance only in FcGRIIb-/- macrophages and attenuated disease severity of cecal ligation and puncture (CLP) sepsis pre-conditioning with sequential LPS injection (LPS-CLP model) only in FcGRIIb-/- mice, but not in WT mice. To summarize, inadequate Lcn-2 production in FcGRIIb-/- macrophage might, at least in part, be responsible for the inordinate LPS tolerance compared with WT cells. Additionally, supplementation of rLcn-2 attenuates LPS tolerance in FcGRIIb-/- macrophages in vitro, and in FcGRIIb-/- mice with LPS-CLP sepsis in vivo. In conclusion, Lcn-2 secreted by macrophages is possibly an autocrine signal to counter the reduced cytokine secretion in LPS tolerance.
Highlights
The functional defect of Fc gamma receptor IIb (FcGRIIb), the only inhibitory receptor amongFcGR family, is one of the genetic causes of systemic lupus erythematosus (SLE) [1,2,3]
The effective organismal control due to the loss of inhibitory signal has been demonstrated in FcGRIIb-/- mice [3,12,13], the extreme exhaustion after repeated stimulations or infections has been mentioned as a possible cause [11,14]
We have recently demonstrated the higher activity of protein kinase C-β Type II in FcGRIIb-/- macrophages with LPS tolerance compared with WT [14]
Summary
The functional defect of Fc gamma receptor IIb (FcGRIIb), the only inhibitory receptor amongFcGR family, is one of the genetic causes of systemic lupus erythematosus (SLE) [1,2,3]. Active lupus induces spontaneous endotoxemia [5,6], which in turn, may cause lipopolysaccharide (LPS) exhaustion [7,8,9,10] resulting in increased infection susceptibility [11]. The effective organismal control due to the loss of inhibitory signal has been demonstrated in FcGRIIb-/- mice [3,12,13], the extreme exhaustion after repeated stimulations or infections has been mentioned as a possible cause [11,14]. The increased infection susceptibility during the immune exhaustion state is well described [15,16,17]. Possibly correlates with the increased infections in lupus [18,19]. Endotoxemia is common in sepsis due to the translocation of LPS from gut into blood circulation due to gut permeability defect [21]
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