Prominent Indomethacin-Induced Enteropathy in Fcgriib Defi-cient lupus Mice: An Impact of Macrophage Responses and Immune Deposition in Gut.

Thansita Bhunyakarnjanarat,Wilasinee Saisorn,Bhumdhanin Chantraprapawat,Peerapat Visitchanakun,Cong Phi Dang,Kanyarat Udompornpitak,Jiraphorn Issara-Amphorn,Asada Leelahavanichkul

doi:10.3390/ijms22031377

Thansita Bhunyakarnjanarat, Wilasinee Saisorn + Show 6 more

Open Access

https://doi.org/10.3390/ijms22031377

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Abstract

A high dose of NSAIDs, a common analgesic, might induce lupus activity through several NSAIDs adverse effects including gastrointestinal permeability defect (gut leakage) and endotoxemia. Indomethacin (25 mg/day) was orally administered for 7 days in 24-wk-old Fc gamma receptor IIb deficient (FcgRIIb-/-) mice, an asymptomatic lupus model (increased anti-dsDNA without lupus nephritis), and age-matched wild-type (WT) mice. Severity of indomethacin-induced enteropathy in FcgRIIb-/- mice was higher than WT mice as demonstrated by survival analysis, intestinal injury (histology, immune-deposition, and intestinal cytokines), gut leakage (FITC-dextran assay and endotoxemia), serum cytokines, and lupus characteristics (anti-dsDNA, renal injury, and proteinuria). Prominent responses of FcgRIIb-/- macrophages toward lipopolysaccharide (LPS) compared to WT cells due to the expression of only activating-FcgRs without inhibitory-FcgRIIb were demonstrated. Extracellular flux analysis indicated the greater mitochondria activity (increased respiratory capacity and respiratory reserve) in FcgRIIb-/- macrophages with a concordant decrease in glycolysis activity when compared to WT cells. In conclusion, gut leakage-induced endotoxemia is more severe in indomethacin-administered FcgRIIb-/- mice than WT, possibly due to the enhanced indomethacin toxicity from lupus-induced intestinal immune-deposition. Due to a lack of inhibitory-FcgRIIb expression, mitochondrial function, and cytokine production of FcgRIIb-/- macrophages were more prominent than WT cells. Hence, lupus disease-activation from NSAIDs-enteropathy-induced gut leakage is possible.

Highlights

A high dose of indomethacin produced more severe intestinal ulcers and enhanced gastro-intestinal permeability defect in 24-wk-old Fc gamma receptor IIb (FcgRIIb)-/- mice compared to wild-type (WT) mice suggesting a prominent adverse effect of Nonsteroidal anti-inflammatory drugs (NSAIDs) in lupus
Our data support that prominent hyperinflammatory responses in FcgRIIb-/- mice compared to WT mice after NSAIDs administration were due to an inability to produce inhibitory FcgRIIb signaling (Figure 11)
Despite the multiple systemic injuries of NSAIDs, the gastrointestinal adverse effect is a most common complication that is resulting in endotoxemia, a potent inflammatory exacerbation factor in lupus [36]

Summary

Introduction

There is an age-dependency in the development of lupus characteristics in FcgRIIb-/- mice, as anti-dsDNA, a major lupus auto-antibody, spontaneously develops in these mice as early as 16–24 wks old [5,6,7]. FcgRIIb-/- mice younger than 24 wks old are asymptomatic because of the undetectable anti-dsDNA [8,9]. The loss of inhibitory signaling in FcgRIIb-/- mice causes lupus, and results in the hyperresponsiveness against pathogen molecules, including lipopolysaccharide (LPS). This is possibly due to the crosstalk of FcgRs (a receptor for Fc portion of immunoglobulin) and TLR-4 (a LPS receptor) [5,8,9,10,11]

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Discussion

Conclusion