Journal
JOURNAL OF INFLAMMATION RESEARCH
Volume 14, Issue -, Pages 2333-2352Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/JIR.S305225
Keywords
FcGRIIB deficient mice; Pristane mice; systemic lupus erythematosus; neutrophil extracellular traps; Candida; gut-leakage
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Funding
- Ratchadapisek Sompoch [CU_GR_63_108_3]
- Program Management Unit for Human Resources & Institutional Development Research and Innovation-CU [B16F630071, B05F630073]
- TSRI Fund [CU_FRB640001_01_23_1]
- National Research Council of Thailand
- The 100th Anniversary Chulalongkorn University Fund for Doctoral Scholarship
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The study explores the impact of gut bacteria and fungi components on lupus severity through inducing neutrophil extracellular traps (NETs). Particularly, in Fc gamma receptor IIB deficient mice, there was more prominent formation of colonic NETs, possibly due to stronger responses against LPS and BG.
Introduction: The translocation of organismal molecules from gut into blood circulation might worsen the disease severity of lupus through the induction of neutrophil extracellular traps (NETs). Methods: An impact of lipopolysaccharide (LPS) and (1 -> 3)-beta-D-glucan (BG), components of gut bacteria and fungi, respectively, on NETs formation, was explored in lupus models, Fc gamma receptor IIB deficiency (FcGRIIB-/-) and Pristane injection, using Candida-administered dextran sulfate solution induced colitis (Candida-DSS) model. Results: Severity of Candida-DSS in FcGRIIB-/- mice was more prominent than wild-type (WT) and Pristane mice as indicated by (i) colonic NETs using immunofluorescence of Ly6G, myeloperoxidase (MPO) and neutrophil elastase (NE) together with expression of PAD4 and IL-1 beta, (ii) colonic immunoglobulin (Ig) deposition (immunofluorescence), (iii) gut-leakage by FITC-dextran assay, endotoxemia and serum BG, (iv) systemic inflammation (neutrophilia, serum cytokines, serum dsDNA and anti-dsDNA) and (v) renal injury (proteinuria, glomerular NETs and Ig deposition). Discussion: The formation of NETs in Candida-DSS mice was more severe than non-Candida-DSS mice and NETs in Candida-DSS were more profound in FcGRIIB-/- mice than Pristane mice. Prominent NETs in Candida-DSS FcGRIIB-/- mice might be due to the profound responses against LPS+BG in FcGRIIB-/- neutrophils compared with WT cells. These data implied an impact of the inhibitory FcGRIIB in NETs formation and an influence of gut fungi in lupus exacerbation. Hence, gut fungi in a DSS-induced gut-leakage lupus model enhanced colonic NETs that facilitated gut translocation of organismal molecules and synergistically exacerbated lupus activity.
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