Sep 28, 2016 - cytopenias, hypercytokinemia, hepatosplenomegaly, and inflammation-induced myelopoiesis, which develop in these models of TLR-driven ...
ABSTRACT NUMBER: 187
Commensal Microbiota Tune Systemic Toll-like ReceptorMediated Inflammatory Responses Lehn K. Weaver1, Chhanda Biswas1 and Edward M. Behrens2, 1Pediatric Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, 2Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA Meeting: 2016 ACR/ARHP Annual Meeting Date of first publication: September 28, 2016 Keywords: macrophage activation syndrome, microbiome, monocytes, systemic lupus erythematosus (SLE) and toll-like receptors
SESSION INFORMATION Date: Sunday, November 13, 2016
Session Type: ACR Poster Session A
Session Title: Innate Immunity and Rheumatic Disease - Poster I
Session Time: 9:00AM-11:00AM
Background/Purpose: Although commensal microbiota are thought to contribute to the development of autoimmunity, the cellular and molecular mechanisms connecting changes in gut microbiota to the development of autoreactive adaptive immune responses remain elusive. Preclinical models of autoimmunity demonstrate reduced disease severity and defective adaptive immune responses in autoimmune-prone mice treated with antibiotics or housed in germ-free conditions. As many autoimmune diseases show evidence of chronic Toll-like receptor (TLR) activation, we posited that defects in TLR-driven innate immune responses may explain the defective adaptive immune responses and reduced disease severity seen in antibiotic-treated mice. Methods: We tested our hypothesis by using two murine models of TLR-driven systemic inflammation in mice treated with or without broad-spectrum antibiotics. Analysis of systemic inflammation was performed 10-14 days after a single dose of pristane (TLR7-driven inflammation) or after 5 doses of CpG (TLR9-driven inflammation) in mice treated with or without antibiotics. Systemic inflammation was determined by analysis of diffuse alveolar hemorrhage, cytopenias, hypercytokinemia, hepatosplenomegaly, and inflammation-induced myelopoiesis, which develop in these models of TLR-driven inflammation. TLR9 responsive cells isolated from mice treated with 0-5 doses of CpG were analyzed for production of IL-12 following ex vivo stimulation with CpG. Results: Mice treated with broad-spectrum antibiotics were protected from developing systemic immunopathology following TLR-driven inflammation in vivo, as evidenced by lack of diffuse alveolar hemorrhage, cytopenias, hypercytokinemia, and hepatosplenomegaly following injection of pristane or repeated doses of CpG. This was not from baseline defects in innate immune cell numbers or TLR responsiveness, as numbers of TLR responsive cells and TLR-driven cytokine production following a single dose of CpG were preserved in antibiotic-treated mice. However, antibiotics abolished the inflammation-induced myelopoiesis and expansion of peripheral TLR pdfcrowd.com
antibiotics abolished the inflammation-induced myelopoiesis and expansion of peripheral TLR responsive monocytes that accompanies both pristane- and CpG- induced immunopathology. Conclusion: We demonstrate that antibiotic-treated mice have normal baseline responses to TLRdriven inflammatory signals, but fail to develop end-organ damage or sustained systemic inflammation to chronic TLR triggers in vivo. Disease protection in antibiotic-treated mice correlated with defective inflammation-induced myelopoiesis and inhibition of peripheral monocyte expansion that drive ongoing TLR immune responses in these models of sustained systemic inflammation. Our data implicate a novel mechanism for how commensal organisms contribute to the development of autoimmunity by tuning systemic innate immune responses in the setting of chronic TLR stimulation. Disclosure: L. K. Weaver, None; C. Biswas, None; E. M. Behrens, None. To cite this abstract in AMA style: Weaver LK, Biswas C, Behrens EM. Commensal Microbiota Tune Systemic Toll-like ReceptorMediated Inflammatory Responses [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/commensal-microbiota-tune-systemic-toll-like-receptormediated-inflammatory-responses/. Accessed November 29, 2016.
ACR Meeting Abstracts - http://acrabstracts.org/abstract/commensal-microbiota-tune-systemictoll-like-receptor-mediated-inflammatory-responses/
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