Cutting Edge: TLR2-Mediated Proinflammatory Cytokine and Chemokine Production by Microglial Cells in Response to Herpes Simplex Virus

Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2005; 175(7):4189-93. DOI: 10.4049/jimmunol.175.7.4189
Source: PubMed


Recent studies indicate that TLRs are critical in generating innate immune responses during infection with HSV-1. In this study, we investigated the role of TLR2 signaling in regulating the production of neuroimmune mediators by examining cytokine and chemokine expression using primary microglial cells obtained from TLR2-/- as well as wild-type mice. Data presented here demonstrate that TLR2 signaling is required for the production of proinflammatory cytokines and chemokines: TNF-alpha, IL-1beta, IL-6, IL-12, CCL7, CCL8, CCL9, CXCL1, CXCL2, CXCL4, and CXCL5. CXCL9 and CXCL10 were also induced by HSV, but their production was not dependent upon TLR2 signaling. Because TLR2-/- mice display significantly reduced mortality and diminished neuroinflammation in response to brain infection with HSV, the TLR2-dependent cytokines identified here might function as key players influencing viral neuropathogenesis.

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Available from: Raj Aravalli, Oct 06, 2015
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    • "Mammalian TLR2 was genetically proven to be indispensable for the eradication of Gram-positive bacteria (Drennan et al., 2004). It has previously been assumed that it might be activated by a broad range of ligands including zymosan, derived from yeast (Sato et al., 2003), glycosylphosphatidylinositols from protozoan parasites (Krishnegowda et al., 2005) and viral glycoproteins (Aravalli et al., 2005; Reske et al., 2008). A critical re-evaluation proved that dior triacetylated lipopetide derived from Gram-positive bacteria are the cognate ligands of mammalian TLR2 (Fischer et al., 2011; Z€ ahringer et al., 2008). "
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    ABSTRACT: The mammalian Toll-like receptor 2 (TLR2) is a dominant receptor for the recognition of Gram-positive bacteria. Its structure and functional properties were unknown in salmonid fish. In RT-PCR and RACE experiments, we obtained the full-length cDNA sequence encoding Tlr2 from rainbow trout (Oncorhynchus mykiss) as well as a copy of an unspliced nonsense message from a highly segmented gene. The primary structure of the encoded receptor complies with the domain structure and ligand-binding sites known from mammals and other fish species and sorts well into the evolutionary tree of teleostean Tlr2s. We retrieved a gene version encoding the receptor on a single exon (tlr2a) and also a partial sequence of a second gene variant being segmented into multiple exons (tlr2b). Surprisingly, the abundances of both transcript variants accounted only for ∼10% of all Tlr2-encoding transcripts in various tissues and cell types of healthy fish. This suggests the expression of several distinct tlr2 gene variants in rainbow trout. We expressed tlr2a in HEK-293 cells, but were unable to demonstrate its functionality through NF-κB activation. Neither synthetic lipopeptides known to stimulate mammalian TLR2 nor different bacterial challenges induced OmTLR2-mediated NF-κB activation, not in HEK-293 or in salmon CHSE-214 cells. Positive demonstration of TLR2-MYD88 interaction excluded that its functional impairment caused the failure of NF-κB activation. We discuss impaired heterodimerization with a necessary Tlr partner as one from among several alternatives to explain the dysfunction of Tlr2a in the interspecies reconstitution system of TLR signaling.
    Developmental and comparative immunology 09/2015; DOI:10.1016/j.dci.2015.08.012 · 2.82 Impact Factor
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    • "To date, the immunological mediators involved in those differential cell processes in the taiep rat remain unknown. Several reports in different animal models [10] [11] [12] [13] [14] [15] and in human patients with MS [16] sustain the involvement of chemokines and their receptors in the CNS inflammation. Alternatively, chemokines also participate in myelin development. "
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    ABSTRACT: Taiep rat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1-and 6-month-old taiep rats. We used a Rat RT 2 Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in the taiep rat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4), which might account for the demyelination in the taiep rat.
    Oxidative Medicine and Cellular Longevity 03/2015; 2015(Article ID 397310,):8. DOI:10.1155/2015/397310 · 3.36 Impact Factor
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    • "CXCL5 has been shown to have a role in CNS diseases, as increased levels of CXCL5 was observed in cerebrospinal fluid during the early hours of ischemic stroke (Zaremba and others 2006). Additionally, dysregulation of CXCL5 expression in response to HSV and JCV was observed in the CNS compartment (Aravalli and others 2005; Darbinyan and others 2013). Together, these studies established a role for CXCL5 in virus-induced CNS diseases. "
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    ABSTRACT: Human immunodeficiency virus-1 (HIV-1)-infected monocytes/macrophages and microglia release increased levels of proinflammatory cytokines and chemokines, including ELR+ (containing glutamic acid-leucine-arginine motif) chemokines. To investigate the role of HIV-1 infection on chemokine regulation, monocyte-derived macrophages (MDMs) from normal donors were infected with HIV-1 and the expression of chemokines and their downstream biological functions were evaluated. Among the tested chemokines, CXCL5 was upregulated significantly both at the mRNA and protein level in the HIV-1-infected MDMs compared with mock-infected cultures. Upregulation of CXCL5 in the HIV-1-infected MDMs is, in part, regulated by increased interleukin-1β (IL-1β) production and phosphorylation of ERK1/2. Functional analyses indicate that HIV-1-induced overexpression of CXCL5 has enhanced the ability to attract neutrophils, as observed by chemotaxis assay. However, exposure of NT2, SH-SY5Y cells, and primary neurons to HIV-1-infected MDM supernatants resulted in cell death that was not rescued by anti-CXCL5 antibody suggesting that CXCL5 does not have direct effect on neuronal death. Together, these results suggest that the increased level of CXCL5 in tissue compartments, including the central nervous system of HIV-1-infected individuals might alter the inflammatory response through the infiltration of neutrophils into tissue compartment, thus causing secondary effects on resident cells.
    Journal of Interferon & Cytokine Research 12/2014; 35(5). DOI:10.1089/jir.2014.0135 · 2.00 Impact Factor
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