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

Chung, Yutein; Zhang, Nan; Wooten, R. Mark

doi:10.1371/journal.pone.0084980

Cited by 46 publications

(56 citation statements)

References 84 publications

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“…Overall, we conclude that there is either redundancy between macrophages, dendritic cells, and neutrophils in their role in controlling B. burgdorferi infection or that B. burgdorferi is adept at evading all of these cells types in vivo. Supporting our conclusion, B. burgdorferi-elicited interleukin-10 (IL-10) suppresses production of proinflammatory mediators and phagocyte-associated events in isolated macrophages and dendritic cells from C57BL/6 mice in vitro, suggesting that suppression of some innate responses is one of many mechanisms B. burgdorferi employs to establish infection (72). Ixodes tick saliva also has an immunosuppressive effect on the host that could play a role in helping B. burgdorferi establish a persistent, disseminated infection within the host under the natural course of infection (73)(74)(75)(76)(77)(78).…”

Section: Discussionsupporting

confidence: 55%

Characterization of Stress and Innate Immunity Resistance of Wild-Type and Δp66 Borrelia burgdorferi

et al. 2018

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is a causative agent of Lyme disease, the most common arthropod-borne disease in the United States. evades host immune defenses to establish a persistent, disseminated infection. Previous work showed that P66-deficient (Δ) is cleared quickly after inoculation in mice. We demonstrate that the Δ strain is rapidly cleared from the skin inoculation site prior to dissemination. The rapid clearance of Δ bacteria is not due to inherent defects in multiple properties that might affect infectivity: bacterial outer membrane integrity, motility, chemotactic response, or nutrient acquisition. This led us to the hypothesis that P66 has a role in mouse cathelicidin-related antimicrobial peptide (mCRAMP; a major skin antimicrobial peptide) and/or neutrophil evasion. Neither wild-type (WT) nor Δ was susceptible to mCRAMP. To examine the role of neutrophil evasion, we administered neutrophil-depleting antibody anti-Ly6G (1A8) to C3H/HeN mice and subsequently monitored the course of infection. Δ mutants were unable to establish infection in neutrophil-depleted mice, suggesting that the important role of P66 during early infection is through another mechanism. Neutrophil depletion did not affect WT bacterial burdens in the skin (inoculation site), ear, heart, or tibiotarsal joint at early time points postinoculation. This was unexpected given that prior studies demonstrated neutrophils phagocytose and kill These data, together with our previous work, suggest that despite the ability of host innate defenses to kill , individual innate immune mechanisms have limited contributions to controlling early infection in the laboratory model used.

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Section: Discussionsupporting

confidence: 55%

Characterization of Stress and Innate Immunity Resistance of Wild-Type and Δp66 Borrelia burgdorferi

et al. 2018

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“…These results and our observation that CD36-deficiency results in reduced IL-12 production by DCs, decreased IFN-␥ responses by NK and T cells at early stages of infection, and early switching from a Th1 to a Th2 are consistent with the notion that CD36 contributes to parasitemia control and resistance to death. Furthermore, it has been shown that IL-10 suppresses the phagocytic activity of Ms and PMNs (69,70). In agreement with these observations, we found that CD36 deficiency causes a substantial increase in IL-10 production.…”

Section: Role Of Cd36 In Malaria Immunitysupporting

confidence: 91%

CD36 receptor regulates malaria-induced immune responses primarily at early blood stage infection contributing to parasitemia control and resistance to mortality

Thylur

Gowda

et al. 2017

Journal of Biological Chemistry

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In malaria, CD36 plays several roles, including mediating parasite sequestration to host organs, phagocytic clearance of parasites, and regulation of immunity. Although the functions of CD36 in parasite sequestration and phagocytosis have been clearly defined, less is known about its role in malaria immunity. Here, to understand the function of CD36 in malaria immunity, we studied parasite growth, innate and adaptive immune responses, and host survival in WT and Cd36 ؊/؊ mice infected with a non-lethal strain of Plasmodium yoelii. Compared with Cd36 ؊/؊ mice, WT mice had lower parasitemias and were resistant to death. At early but not at later stages of infection, WT mice had higher circulatory proinflammatory cytokines and lower anti-inflammatory cytokines than Cd36 ؊/؊ mice. WT mice showed higher frequencies of proinflammatory cytokineproducing and lower frequencies of anti-inflammatory cytokine-producing dendritic cells (DCs) and natural killer cells than Cd36 ؊/؊ mice. Cytokines produced by co-cultures of DCs from infected mice and ovalbumin-specific, MHC class II-restricted ␣/␤ (OT-II) T cells reflected CD36-dependent DC function. WT mice also showed increased Th1 and reduced Th2 responses compared with Cd36 ؊/؊ mice, mainly at early stages of infection. Furthermore, in infected WT mice, macrophages and neutrophils expressed higher levels of phagocytic receptors and showed enhanced phagocytosis of parasite-infected erythrocytes than those in Cd36 ؊/؊ mice in an IFN-␥-dependent manner. However, there were no differences in malaria-induced humoral responses between WT and Cd36 ؊/؊ mice. Overall, the results show that CD36 plays a significant role in controlling parasite burden by contributing to proinflammatory cytokine responses by DCs and natural killer cells, Th1 development, phagocytic receptor expression, and phagocytic activity. . 5 The abbreviations used are: DC, dendritic cell; IRBC, infected red blood cell; PfEMP1, P. falciparum erythrocyte membrane protein-1; M, macrophage; PMN, polymorphonuclear neutrophil; BMDM, M-CSF-differentiated mouse bone marrow cell; CR1/CR2, complement receptors 1 and 2Based on the results presented in Fig. 1, we predicted that CD36 contributes to malaria-induced immune responses that are involved in parasitemia control and resistance to disease Role of CD36 in malaria immunity

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“…After 24 hours of treatment with B. burgdorferi , three cytokines, IL-1β, IL-6 and IL-12, and the neutrophil chemokine CXCL1, were more abundant in B6 miR-146a −/− cell supernatant than in B6 cell supernatant, consistent with hyperactive NF-κB activation and transcript analysis (Table 3). Interestingly, TNFα, an early-response NF-κB cytokine, did not share this trend, which may be due to the relatively late time point used for this analysis [65]. Production of IL-10 was robust in both strains, although somewhat greater in miR-146a-deficient BMDMs.…”

Section: Resultsmentioning

confidence: 92%

MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi

Lochhead

Zachary

et al. 2014

PLoS Pathog

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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.

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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

Cited by 46 publications

References 84 publications

Characterization of Stress and Innate Immunity Resistance of Wild-Type and Δp66 Borrelia burgdorferi

Characterization of Stress and Innate Immunity Resistance of Wild-Type and Δp66 Borrelia burgdorferi

CD36 receptor regulates malaria-induced immune responses primarily at early blood stage infection contributing to parasitemia control and resistance to mortality

MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi

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