Fc Gamma Receptor IIB Deficient Mice: A Lupus Model with Increased Endotoxin Tolerance-Related Sepsis Susceptibility
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Published on: May 2, 2018
Thunnicha Ondee1, Saowapha Surawut, Sujittra Taratummarat
1*Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand †Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Bangkok, Thailand ‡Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand §Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand ||Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand ¶Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand #Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand **STAR on Craniofacial and Skeleton Disorders, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
Abstract:
Hyper-elevated immune response of FcGRIIb-/- mice, a lupus model with an inhibitory-signaling defect, can become exhausted (less subsequent immune-response than the first response) with sequential lipopolysaccharide (LPS) stimulation. Endotoxin tolerance-related modifications of inflammatory response were investigated in FcGRIIb-/- mice in both an in vivo sepsis model and in vitro using cultured macrophages. Serum cytokine concentrations, after the second LPS injection (at 5-fold higher levels than the first dose), did not exceed the first dose levels in either FcGRIIb-/- or wild-type mice. These data indicated an endotoxin-tolerance response in both genetic backgrounds. However, the difference of cytokine levels between the first and second LPS injection was more prominent in FcGRIIb-/- mice. More importantly, CLP-induced sepsis after LPS-preconditioning (two separated doses of LPS administration) was more severe in FcGRIIb-/- mice (as measured by mortality rate, bacteria count in blood, serum cytokines, creatinine, and alanine transaminase). An attenuated response was demonstrated after two sequential LPS stimulations of bone-marrow-derived macrophages. Cytokine production was reduced and lower bacterial killing activity occurred with macrophages from FcGRIIb-/- mice relative to wild-type macrophages. Thus, there is a more prominent effect of endotoxin-tolerance in FcGRIIb-/- macrophages relative to wild-type. In conclusion, repeated-LPS administrations induced quantitatively greater endotoxin-tolerance responses in FcGRIIb-/- mice both in vivo and in vitro. Endotoxin-tolerance in vivo was associated with more severe sepsis, at least in part, due to macrophage-dysfunction.
