MicroRNAs have been shown to be important regulators of inflammatory and immune responses and are implicated in several immune disorders including systemic lupus erythematosus and rheumatoid arthritis, but their role in Lyme borreliosis remains unknown. We performed a microarray screen for expression of miRNAs in joint tissue from three mouse strains infected with Borrelia burgdorferi. This screen identified upregulation of miR-146a, a key negative regulator of NF-κB signaling, in all three strains, suggesting it plays an important role in the in vivo response to B. burgdorferi. Infection of B6 miR-146a？/？ mice with B. burgdorferi revealed a critical nonredundant role of miR-146a in modulating Lyme arthritis without compromising host immune response or heart inflammation. The impact of miR-146a was specifically localized to the joint, and did not impact lesion development or inflammation in the heart. Furthermore, B6 miR-146a？/？ mice had elevated levels of NF-κB-regulated products in joint tissue and serum late in infection. Flow cytometry analysis of various lineages isolated from infected joint tissue of mice showed that myeloid cell infiltration was significantly greater in B6 miR-146a？/？ mice, compared to B6, during B. burgdorferi infection. Using bone marrow-derived macrophages, we found that TRAF6, a known target of miR-146a involved in NF-κB activation, was dysregulated in resting and B. burgdorferi-stimulated B6 miR-146a？/？ macrophages, and corresponded to elevated IL-1β, IL-6 and CXCL1 production. This dysregulated protein production was also observed in macrophages treated with IL-10 prior to B. burgdorferi stimulation. Peritoneal macrophages from B6 miR-146a？/？ mice also showed enhanced phagocytosis of B. burgdorferi. Together, these data show that miR-146a-mediated regulation of TRAF6 and NF-κB, and downstream targets such as IL-1β, IL-6 and CXCL1, are critical for modulation of Lyme arthritis during chronic infection with B. burgdorferi.
References
[1]
Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, et al. (1982) Lyme disease-a tick-borne spirochetosis? Science 216: 1317–1319. doi: 10.1126/science.7043737
[2]
Kuehn BM (2013) CDC estimates 300,000 US cases of Lyme disease annually. JAMA 310: 1110. doi: 10.1001/jama.2013.278331
[3]
Steere AC, Glickstein L (2004) Elucidation of Lyme arthritis. Nat Rev Immunol 4: 143–152. doi: 10.1038/nri1267
[4]
Steere AC, Schoen RT, Taylor E (1987) The clinical evolution of Lyme arthritis. Ann Intern Med 107: 725–731. doi: 10.7326/0003-4819-107-5-725
[5]
Drouin EE, Seward RJ, Strle K, McHugh G, Katchar K, et al. (2013) A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease. Arthritis Rheum 65: 186–196. doi: 10.1002/art.37732
[6]
Duray PH, Steere AC (1988) Clinical pathologic correlations of Lyme disease by stage. Ann N Y Acad Sci 539: 65–79. doi: 10.1111/j.1749-6632.1988.tb31839.x
[7]
Barthold SW, Beck DS, Hansen GM, Terwilliger GA, Moody KD (1990) Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis 162: 133–138. doi: 10.1093/infdis/162.1.133
[8]
Barthold SW, Persing DH, Armstrong AL, Peeples RA (1991) Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol 139: 263–273.
[9]
Brown JP, Zachary JF, Teuscher C, Weis JJ, Wooten RM (1999) Dual role of interleukin-10 in murine Lyme disease: regulation of arthritis severity and host defense. Infect Immun 67: 5142–5150.
[10]
Ma Y, Seiler KP, Eichwald EJ, Weis JH, Teuscher C, et al. (1998) Distinct characteristics of resistance to Borrelia burgdorferi-induced arthritis in C57BL/6N mice. Infect Immun 66: 161–168.
[11]
DiDonato JA, Mercurio F, Karin M (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246: 379–400. doi: 10.1111/j.1600-065x.2012.01099.x
[12]
Weis JJ, Ma Y, Erdile LF (1994) Biological activities of native and recombinant Borrelia burgdorferi outer surface protein A: dependence on lipid modification. Infect Immun 62: 4632–4636.
[13]
Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, et al. (1999) Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol 163: 2382–2386.
[14]
Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, et al. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8: 878–884. doi: 10.1038/nm732
[15]
Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, et al. (1999) Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285: 736–739. doi: 10.1126/science.285.5428.736
[16]
Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, et al. (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732–736. doi: 10.1126/science.285.5428.732
[17]
Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, et al. (2002) Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol 168: 348–355. doi: 10.4049/jimmunol.168.1.348
[18]
Bolz DD, Sundsbak RS, Ma Y, Akira S, Kirschning CJ, et al. (2004) MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J Immunol 173: 2003–2010. doi: 10.4049/jimmunol.173.3.2003
[19]
Liu N, Montgomery RR, Barthold SW, Bockenstedt LK (2004) Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun 72: 3195–3203. doi: 10.1128/iai.72.6.3195-3203.2004
[20]
Behera AK, Hildebrand E, Bronson RT, Perides G, Uematsu S, et al. (2006) MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi. Infect Immun 74: 1462–1470. doi: 10.1128/iai.74.3.1462-1470.2006
[21]
Bockenstedt LK, Liu N, Schwartz I, Fish D (2006) MyD88 deficiency enhances acquisition and transmission of Borrelia burgdorferi by Ixodes scapularis ticks. Infect Immun 74: 2154–2160. doi: 10.1128/iai.74.4.2154-2160.2006
[22]
Ruland J (2011) Return to homeostasis: downregulation of NF-kappaB responses. Nat Immunol 12: 709–714. doi: 10.1038/ni.2055
[23]
Boldin MP, Baltimore D (2012) MicroRNAs, new effectors and regulators of NF-kappaB. Immunol Rev 246: 205–220. doi: 10.1111/j.1600-065x.2011.01089.x
[24]
Hu R, O'Connell RM (2013) MicroRNA control in the development of systemic autoimmunity. Arthritis Res Ther 15: 202. doi: 10.1186/ar4131
[25]
Yates LA, Norbury CJ, Gilbert RJ (2013) The long and short of microRNA. Cell 153: 516–519. doi: 10.1016/j.cell.2013.04.003
[26]
O'Neill LA, Sheedy FJ, McCoy CE (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11: 163–175. doi: 10.1038/nri2957
[27]
Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103: 12481–12486. doi: 10.1073/pnas.0605298103
[28]
Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, et al. (2011) NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A 108: 9184–9189. doi: 10.1073/pnas.1105398108
[29]
Zhao JL, Rao DS, O'Connell RM, Garcia-Flores Y, Baltimore D (2013) MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice. Elife 2: e00537. doi: 10.7554/elife.00537
[30]
Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, et al. (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208: 1189–1201. doi: 10.1084/jem.20101823
[31]
Yang L, Boldin MP, Yu Y, Liu CS, Ea CK, et al. (2012) miR-146a controls the resolution of T cell responses in mice. J Exp Med 209: 1655–1670. doi: 10.1084/jem.20112218
[32]
Chan EK, Ceribelli A, Satoh M (2013) MicroRNA-146a in autoimmunity and innate immune responses. Ann Rheum Dis 72 Suppl 2: ii90–95. doi: 10.1136/annrheumdis-2012-202203
[33]
Luo X, Yang W, Ye DQ, Cui H, Zhang Y, et al. (2011) A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS Genet 7: e1002128. doi: 10.1371/journal.pgen.1002128
[34]
Tang Y, Luo X, Cui H, Ni X, Yuan M, et al. (2009) MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60: 1065–1075. doi: 10.1002/art.24436
[35]
Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, et al. (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58: 1284–1292. doi: 10.1002/art.23429
[36]
Stanczyk J, Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, et al. (2008) Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58: 1001–1009. doi: 10.1002/art.23386
[37]
Miyaki S, Asahara H (2012) Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol 8: 543–552. doi: 10.1038/nrrheum.2012.128
[38]
Yamasaki K, Nakasa T, Miyaki S, Ishikawa M, Deie M, et al. (2009) Expression of MicroRNA-146a in osteoarthritis cartilage. Arthritis Rheum 60: 1035–1041. doi: 10.1002/art.24404
[39]
Hu R, Huffaker TB, Kagele DA, Runtsch MC, Bake E, et al. (2013) MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J Immunol 190: 5972–5980. doi: 10.4049/jimmunol.1300351
[40]
O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, et al. (2010) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33: 607–619. doi: 10.1016/j.immuni.2010.09.009
[41]
O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, et al. (2008) Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 205: 585–594. doi: 10.1084/jem.20072108
[42]
McCoy CE, Sheedy FJ, Qualls JE, Doyle SL, Quinn SR, et al. (2010) IL-10 inhibits miR-155 induction by toll-like receptors. J Biol Chem 285: 20492–20498. doi: 10.1074/jbc.m110.102111
[43]
Lochhead RB, Sonderegger FL, Ma Y, Brewster JE, Cornwall D, et al. (2012) Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine Lyme disease and are major sources of chemokines in Borrelia burgdorferi-infected joint tissue. J Immunol 189: 2488–2501. doi: 10.4049/jimmunol.1201095
[44]
Miller JC, Ma Y, Bian J, Sheehan KC, Zachary JF, et al. (2008) A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice. J Immunol 181: 8492–8503. doi: 10.4049/jimmunol.181.12.8492
[45]
Bramwell KK, Ma Y, Weis JH, Chen X, Zachary JF, et al. (2014) Lysosomal beta-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124: 311–320. doi: 10.1172/jci72339
[46]
Brown CR, Lai AY, Callen ST, Blaho VA, Hughes JM, et al. (2008) Adenoviral delivery of interleukin-10 fails to attenuate experimental Lyme disease. Infect Immun 76: 5500–5507. doi: 10.1128/iai.00808-08
[47]
Crandall H, Dunn DM, Ma Y, Wooten RM, Zachary JF, et al. (2006) Gene expression profiling reveals unique pathways associated with differential severity of lyme arthritis. J Immunol 177: 7930–7942. doi: 10.4049/jimmunol.177.11.7930
[48]
Sonderegger FL, Ma Y, Maylor-Hagan H, Brewster J, Huang X, et al. (2012) Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-gamma-mediated Lyme arthritis. J Immunol 188: 1381–1393. doi: 10.4049/jimmunol.1102359
Ruderman EM, Kerr JS, Telford SR 3rd, Spielman A, Glimcher LH, et al. (1995) Early murine Lyme carditis has a macrophage predominance and is independent of major histocompatibility complex class II-CD4+ T cell interactions. J Infect Dis 171: 362–370. doi: 10.1093/infdis/171.2.362
[51]
Montgomery RR, Booth CJ, Wang X, Blaho VA, Malawista SE, et al. (2007) Recruitment of macrophages and polymorphonuclear leukocytes in Lyme carditis. Infect Immun 75: 613–620. doi: 10.1128/iai.00685-06
[52]
Centers for Disease C, Prevention (2013) Three sudden cardiac deaths associated with Lyme carditis - United States, November 2012–July 2013. MMWR Morb Mortal Wkly Rep 62: 993–996.
[53]
Antonara S, Chafel RM, LaFrance M, Coburn J (2007) Borrelia burgdorferi adhesins identified using in vivo phage display. Mol Microbiol 66: 262–276. doi: 10.1111/j.1365-2958.2007.05924.x
[54]
Coburn J, Leong J, Chaconas G (2013) Illuminating the roles of the Borrelia burgdorferi adhesins. Trends Microbiol 21: 372–379. doi: 10.1016/j.tim.2013.06.005
[55]
Olson CM Jr, Bates TC, Izadi H, Radolf JD, Huber SA, et al. (2009) Local production of IFN-gamma by invariant NKT cells modulates acute Lyme carditis. J Immunol 182: 3728–3734. doi: 10.4049/jimmunol.0804111
[56]
Schilling JD, Machkovech HM, Kim AH, Schwendener R, Schaffer JE (2012) Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366–1373. doi: 10.1152/ajpheart.00111.2012
[57]
Rymarchyk SL, Lowenstein H, Mayette J, Foster SR, Damby DE, et al. (2008) Widespread natural variation in murine natural killer T-cell number and function. Immunology 125: 331–343. doi: 10.1111/j.1365-2567.2008.02846.x
[58]
Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, et al. (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40: 91–104. doi: 10.1016/j.immuni.2013.11.019
[59]
Kelleher Doyle M, Telford SR 3rd, Criscione L, Lin SR, Spielman A, et al. (1998) Cytokines in murine lyme carditis: Th1 cytokine expression follows expression of proinflammatory cytokines in a susceptible mouse strain. J Infect Dis 177: 242–246. doi: 10.1086/517364
[60]
Brown CR, Blaho VA, Fritsche KL, Loiacono CM (2006) Stat1 deficiency exacerbates carditis but not arthritis during experimental lyme borreliosis. J Interferon Cytokine Res 26: 390–399. doi: 10.1089/jir.2006.26.390
[61]
Brown CR, Blaho VA, Loiacono CM (2003) Susceptibility to experimental Lyme arthritis correlates with KC and monocyte chemoattractant protein-1 production in joints and requires neutrophil recruitment via CXCR2. J Immunol 171: 893–901. doi: 10.4049/jimmunol.171.2.893
[62]
Ritzman AM, Hughes-Hanks JM, Blaho VA, Wax LE, Mitchell WJ, et al. (2010) The chemokine receptor CXCR2 ligand KC (CXCL1) mediates neutrophil recruitment and is critical for development of experimental Lyme arthritis and carditis. Infect Immun 78: 4593–4600. doi: 10.1128/iai.00798-10
[63]
Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, et al. (2009) Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-beta. PLoS Pathog 5: e1000444. doi: 10.1371/journal.ppat.1000444
[64]
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23–35. doi: 10.1038/nri978
[65]
Chung Y, Zhang N, Wooten RM (2013) Borrelia burgdorferi elicited-IL-10 suppresses the production of inflammatory mediators, phagocytosis, and expression of co-stimulatory receptors by murine macrophages and/or dendritic cells. PLoS One 8: e84980. doi: 10.1371/journal.pone.0084980
[66]
Dennis VA, Jefferson A, Singh SR, Ganapamo F, Philipp MT (2006) Interleukin-10 anti-inflammatory response to Borrelia burgdorferi, the agent of Lyme disease: a possible role for suppressors of cytokine signaling 1 and 3. Infect Immun 74: 5780–5789. doi: 10.1128/iai.00678-06
[67]
Gautam A, Dixit S, Philipp MT, Singh SR, Morici LA, et al. (2011) Interleukin-10 alters effector functions of multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation. Infect Immun 79: 4876–4892. doi: 10.1128/iai.05451-11
[68]
Gautam A, Dixit S, Embers M, Gautam R, Philipp MT, et al. (2012) Different patterns of expression and of IL-10 modulation of inflammatory mediators from macrophages of Lyme disease-resistant and -susceptible mice. PLoS One 7: e43860. doi: 10.1371/journal.pone.0043860
[69]
O'Connell RM, Rao DS, Baltimore D (2012) microRNA regulation of inflammatory responses. Annu Rev Immunol 30: 295–312. doi: 10.1146/annurev-immunol-020711-075013
[70]
Meijer HA, Kong YW, Lu WT, Wilczynska A, Spriggs RV, et al. (2013) Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340: 82–85. doi: 10.1126/science.1231197
[71]
Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11: 113–127. doi: 10.1038/nrm2838
[72]
Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36: 503–514. doi: 10.1016/j.immuni.2012.03.013
[73]
Tanaka T, Soriano MA, Grusby MJ (2005) SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 22: 729–736. doi: 10.1016/j.immuni.2005.04.008
[74]
Butler MP, Hanly JA, Moynagh PN (2007) Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases. J Biol Chem 282: 29729–29737. doi: 10.1074/jbc.m704558200
[75]
Petnicki-Ocwieja T, Chung E, Acosta DI, Ramos LT, Shin OS, et al. (2013) TRIF mediates Toll-like receptor 2-dependent inflammatory responses to Borrelia burgdorferi. Infect Immun 81: 402–410. doi: 10.1128/iai.00890-12
[76]
Hawley KL, Martin-Ruiz I, Iglesias-Pedraz JM, Berwin B, Anguita J (2013) CD14 targets complement receptor 3 to lipid rafts during phagocytosis of Borrelia burgdorferi. Int J Biol Sci 9: 803–810. doi: 10.7150/ijbs.7136
[77]
Hawley KL, Olson CM Jr, Iglesias-Pedraz JM, Navasa N, Cervantes JL, et al. (2012) CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis of Borrelia burgdorferi. Proc Natl Acad Sci U S A 109: 1228–1232. doi: 10.1073/pnas.1112078109
[78]
Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, et al. (2011) Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-beta. Proc Natl Acad Sci U S A 108: 3683–3688. doi: 10.1073/pnas.1013776108
[79]
Shin OS, Isberg RR, Akira S, Uematsu S, Behera AK, et al. (2008) Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction. Infect Immun 76: 2341–2351. doi: 10.1128/iai.01600-07
[80]
Armstrong AL, Barthold SW, Persing DH, Beck DS (1992) Carditis in Lyme disease susceptible and resistant strains of laboratory mice infected with Borrelia burgdorferi. Am J Trop Med Hyg 47: 249–258.
[81]
Weis JJ, McCracken BA, Ma Y, Fairbairn D, Roper RJ, et al. (1999) Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. J Immunol 162: 948–956.
[82]
Roper RJ, Weis JJ, McCracken BA, Green CB, Ma Y, et al. (2001) Genetic control of susceptibility to experimental Lyme arthritis is polygenic and exhibits consistent linkage to multiple loci on chromosome 5 in four independent mouse crosses. Genes Immun 2: 388–397. doi: 10.1038/sj.gene.6363801
[83]
Wang G, Ma Y, Buyuk A, McClain S, Weis JJ, et al. (2004) Impaired host defense to infection and Toll-like receptor 2-independent killing of Borrelia burgdorferi clinical isolates in TLR2-deficient C3H/HeJ mice. FEMS Microbiol Lett 231: 219–225. doi: 10.1016/s0378-1097(03)00960-1
[84]
Barthold SW, Feng S, Bockenstedt LK, Fikrig E, Feen K (1997) Protective and arthritis-resolving activity in sera of mice infected with Borrelia burgdorferi. Clin Infect Dis 25 Suppl 1: S9–17. doi: 10.1086/516166
[85]
Bockenstedt LK, Kang I, Chang C, Persing D, Hayday A, et al. (2001) CD4+ T helper 1 cells facilitate regression of murine Lyme carditis. Infect Immun 69: 5264–5269. doi: 10.1128/iai.69.9.5264-5269.2001
[86]
Anguita J, Samanta S, Revilla B, Suk K, Das S, et al. (2000) Borrelia burgdorferi gene expression in vivo and spirochete pathogenicity. Infect Immun 68: 1222–1230. doi: 10.1128/iai.68.3.1222-1230.2000
[87]
Baumjohann D, Ansel KM (2013) MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 13: 666–678. doi: 10.1038/nri3494
[88]
Bezman NA, Chakraborty T, Bender T, Lanier LL (2011) miR-150 regulates the development of NK and iNKT cells. J Exp Med 208: 2717–2731. doi: 10.1084/jem.20111386
[89]
Zheng Q, Zhou L, Mi QS (2012) MicroRNA miR-150 is involved in Valpha14 invariant NKT cell development and function. J Immunol 188: 2118–2126. doi: 10.4049/jimmunol.1103342
[90]
Zietara N, Lyszkiewicz M, Witzlau K, Naumann R, Hurwitz R, et al. (2013) Critical role for miR-181a/b-1 in agonist selection of invariant natural killer T cells. Proc Natl Acad Sci U S A 110: 7407–7412. doi: 10.1073/pnas.1221984110
[91]
Nahid MA, Pauley KM, Satoh M, Chan EK (2009) miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY. J Biol Chem 284: 34590–34599. doi: 10.1074/jbc.m109.056317
[92]
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al. (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142: 914–929. doi: 10.1016/j.cell.2010.08.012
[93]
Hamilton T, Li X, Novotny M, Pavicic PG Jr, Datta S, et al. (2012) Cell type- and stimulus-specific mechanisms for post-transcriptional control of neutrophil chemokine gene expression. J Leukoc Biol 91: 377–383. doi: 10.1189/jlb.0811404
[94]
Oosting M, van de Veerdonk FL, Kanneganti TD, Sturm P, Verschueren I, et al. (2011) Borrelia species induce inflammasome activation and IL-17 production through a caspase-1-dependent mechanism. Eur J Immunol 41: 172–181. doi: 10.1002/eji.201040385
[95]
Moore MW, Cruz AR, LaVake CJ, Marzo AL, Eggers CH, et al. (2007) Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production. Infect Immun 75: 2046–2062. doi: 10.1128/iai.01666-06
[96]
Strle K, Shin JJ, Glickstein LJ, Steere AC (2012) Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis. Arthritis Rheum 64: 1497–1507. doi: 10.1002/art.34383
[97]
Shin JJ, Glickstein LJ, Steere AC (2007) High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis. Arthritis Rheum 56: 1325–1335. doi: 10.1002/art.22441
[98]
Meerpohl HG, Lohmann-Matthes ML, Fischer H (1976) Studies on the activation of mouse bone marrow-derived macrophages by the macrophage cytotoxicity factor (MCF). Eur J Immunol 6: 213–217. doi: 10.1002/eji.1830060313
[99]
Carroll JA, Stewart PE, Rosa P, Elias AF, Garon CF (2003) An enhanced GFP reporter system to monitor gene expression in Borrelia burgdorferi. Microbiology 149: 1819–1828. doi: 10.1099/mic.0.26165-0
[100]
Lazarus JJ, Kay MA, McCarter AL, Wooten RM (2008) Viable Borrelia burgdorferi enhances interleukin-10 production and suppresses activation of murine macrophages. Infect Immun 76: 1153–1162. doi: 10.1128/iai.01404-07
