Lyme arthritis results from the localized inflammatory response to Borrelia burgdorferi infection of joint tissue. This arthritis can be studied in mice, with certain strains (C3H) developing severe arthritis at 4 wks of infection while other strains (B6) develop mild disease. Lipoproteins from B. burgdorferi are potent stimulants of inflammatory responses, through their interaction with TLR2. In the previous award, TLR2 was found to play a critical role in host defense;however, it was found to be dispensable for arthritis development. To identify inflammatory pathways that were activated following infection of joint tissue by B. burgdorferi, global gene expression analysis was performed using Affymetrix GeneChip arrays. Two distinct profiles were identified in mice displaying different disease phenotypes: a pro-inflammatory IFN-dependent profile occurred in joint tissue of C3H mice early in response to the invading B. burgdorferi whereas, an entirely distinct set of genes, involved in epidermal development and wound repair, were upregulated in the mildly arthritic B6 mice. B6 mice deficient in the anti-inflammatory cytokine IL-10 developed more severe arthritis than wild type B6 mice upon infection with B. burgdorferi, and assumed gene expression profiles similar to C3H mice. This supports the association of the IFN profile with severe Lyme arthritis, as do blocking studies in C3H mice with antibodies to the Type I IFN receptor.
In Aim 1 of this application, the relative contribution of Type I and II IFNs to initiation and maintenance of severe arthritis in C3H mice will be determined. Depletion experiments suggest that the cell types responsible for the earliest induction of IFN are plasmacytoid DCs, pDCs, perhaps working in concert with synovial fibroblasts. Analysis of cells recovered from arthritic tissues and surrounding skin will be used to identify the cell type responsible and the signaling pathway involved in IFN induction, using magnetic bead purification, RT-PCR analysis of gene induction, and siRNA silencing of bacterial sensors.
In Aim 2, the tissue and cellular source of IL-10 that suppresses arthritis in B6 mice will be identified. IL-10 production in tissues and cells recovered from infected mice will be assessed and radiation chimeras will be developed. These experiments will identify the involvement of hematopoietic and/or resident cells of the joint or skin to the IL-10 mediated suppression of arthritis and to induction of the epidermal profile. Cell types expressing IL-10 in infected B6 mice will be identified, with depletion and reconstitution performed to confirm their involvement. Preliminary results suggest that IFN producing pDCs may play a critical role in induction of arthritis in C3H mice while the early recruitment/expansion of IL-10 producing myeloid DCs, mDCs, may suppress disease development in B6 mice. It is possible that distinct sensors/receptors and cell types are may be involved in the pro- verses anti-inflammatory response. Characterization of these interactions could have profound implication on the development of novel therapies for inflammatory pathologies. Project Narrative: Two distinct types of responses have been identified in mice infected with the agent of Lyme disease, Borrelia burgdorferi. One pathway is similar to that seen in lupus, and promotes the development of severe arthritis, while the other pathway is associated with reduced arthritis severity. Understanding how distinct responses that influence disease outcome are activated by the same bacterial pathogen has global implications for understanding the development and control of inflammatory pathologies.
|Lochhead, Robert B; Ma, Ying; Zachary, James F et al. (2014) MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi. PLoS Pathog 10:e1004212|
|Ma, Ying; Bramwell, Kenneth K C; Lochhead, Robert B et al. (2014) Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. J Immunol 193:6050-60|
|Debnath, Irina; Roundy, Kirstin M; Pioli, Peter D et al. (2013) Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins. Int Immunol 25:99-115|
|Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2012) High-throughput genotyping of advanced congenic lines by high resolution melting analysis for identification of Bbaa2, a QTL controlling Lyme arthritis. Biotechniques 52:183-90|
|Dahlem, Timothy; Cho, Scott; Spangrude, Gerald J et al. (2012) Overexpression of Snai3 suppresses lymphoid- and enhances myeloid-cell differentiation. Eur J Immunol 42:1038-43|
|Sonderegger, F Lynn; Ma, Ying; Maylor-Hagan, Heather et al. (2012) Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-?-mediated Lyme arthritis. J Immunol 188:1381-93|
|Roundy, Kirstin M; Jacobson, Amanda C; Weis, Janis J et al. (2010) The in vitro derivation of phenotypically mature and diverse B cells from immature spleen and bone marrow precursors. Eur J Immunol 40:1139-49|
|Miller, Jennifer C; Maylor-Hagen, Heather; Ma, Ying et al. (2010) The Lyme disease spirochete Borrelia burgdorferi utilizes multiple ligands, including RNA, for interferon regulatory factor 3-dependent induction of type I interferon-responsive genes. Infect Immun 78:3144-53|
|Jacobson, Amanda C; Weis, Janis J; Weis, John H (2009) CD21 signaling via C3 regulates Purkinje cell protein 4 expression. Mol Immunol 46:1488-93|
|Koening, Curry L; Miller, Jennifer C; Nelson, Jenifer M et al. (2009) Toll-like receptors mediate induction of hepcidin in mice infected with Borrelia burgdorferi. Blood 114:1913-8|
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