Endotoxemia from NSAIDS-induced gut-leakage enhanced lupus characteristics in Fc gamma receptor iib deficient lupus mice

Abstract

High dose of non-steroidal anti-inflammatory drugs (NSAIDs), the common analgesia, might induce lupus activity through NSAIDs-induced gastrointestinal permeability defect (gut leakage) that causes endotoxemia. Indomethacin (25 mg/day) was orally administered for 7 days in 24-week-old Fc gamma receptor IIb deficient (FcgRIIb-/-) mice, an asymptomatic lupus model, and age-matched wild-type (WT) mice. The severity of indomethacin-induced enteropathy in FcgRIIb-/- mice was higher than WT mice as demonstrated by intestinal injury (histology, immune-deposition and intestinal cytokines), gut leakage (FITC-dextran assay and endotoxemia) and serum cytokines. In addition, higher responses against endotoxemia in indomethacin-administered FcgRIIb-/- mice was also supported by the prominent responses of FcgRIIb-/- bone marrow-derived macrophages toward lipopolysaccharide (LPS) compared to WT macrophages. LPS induces the expression of both activating-FcgRs (FcgRIII and FcgRIV) and inhibitory-FcgRIIb in WT macrophages, while enhanced only activating FcgRs in FcgRIIb-/- mice cells. In conclusion, gut leakage-induced endotoxemia is more severe in NSAIDs-administered FcgRIIb-/- mice when compared with WT. Due to a lack of inhibitory FcgRIIb expression, cytokine production from FcgRIIb-/- macrophages were more prominent than the WT cells. Hence, lupus disease activation from NSAIDs-induced gut leakage is possible through NSAIDs enteropathy.