Session Type: Abstract Submissions
Session Time: 2:00PM-3:00PM
Methods: Broad-spectrum antibiotics were administered to C57BL/6 wild-type mice via their drinking water for 3 weeks prior to the induction of TLR9-mediated MAS. TLR9-mediated MAS was induced by intraperitoneal injection of CpG1826 into antibiotic-treated and control mice every other day for 5 doses. Systemic inflammation was determined 24 hours after the last dose of CpG by analysis of cytopenias, hypercytokinemia, hepatosplenomegaly, peripheral monocytosis, and inflammation-induced myelopoiesis. Initial TLR9 responses in antibiotic-treated and control mice were measured 24 hours after a single dose of CpG1826. Baseline numbers of TLR9 responsive monocytes and myeloid progenitors were enumerated in antibiotic-treated and control mice. The function of myeloid progenitors from antibiotic-treated and control mice were tested using in vitro myelopoiesis assays.
Results : Antibiotic-treated mice are completely protected from TLR9-induced MAS. Disease protection is not mediated by defective baseline TLR9 responses, as monocytes are present in antibiotic-treated mice and mount a normal inflammatory response to the initial TLR9 stimulus. Instead, disease protection correlates with failed induction of myelopoiesis and impaired peripheral monocyte accumulation. Baseline numbers and function of myeloid progenitors are reduced in antibiotic-treated mice, which correlates with reduced levels of serum myeloid-specific growth factors.
Conclusion : Our data suggest that microbiota-dependent signals sustain chronic TLR9-driven inflammation and immunopathology by promoting effective inflammatory myelopoiesis. These data implicate microbiota as a central pathogenic contributor to chronic inflammation, and provide rationale for future attempts to target microbiota-dependent regulation of inflammatory myelopoiesis for therapeutic benefit in TLR-driven chronic rheumatic diseases.
To cite this abstract in AMA style:Weaver LK, Biswas C, Chu N, Behrens EM. Microbiota-Dependent Signals Regulate Inflammatory Myelopoiesis in a Murine Model of Macrophage Activation Syndrome [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 4). http://acrabstracts.org/abstract/microbiota-dependent-signals-regulate-inflammatory-myelopoiesis-in-a-murine-model-of-macrophage-activation-syndrome/. Accessed October 20, 2017.
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/microbiota-dependent-signals-regulate-inflammatory-myelopoiesis-in-a-murine-model-of-macrophage-activation-syndrome/