Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection

Bardina, Susana V.; Michlmayr, Daniela; Hoffman, Kevin W.; Obara, Christopher J.; Sum, Janet; Charo, Israel F.; Lu, Wuyuan; Pletnev, Alexander G.; Lim, Jean K.

doi:10.4049/jimmunol.1500352

Cited by 80 publications

(91 citation statements)

References 71 publications

(81 reference statements)

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“…CCL2 and CCL7 are important inflammatory chemokines that recruit monocytes to specified lesions, promote the release of local inflammatory factors and aggravate the inflammatory response (22,23). In the present study, the results from RT-qPCR suggested that levels of CCL2 and CCL7 mRNA were significantly increased in the peripheral blood of patients with DVT compared with the controls (P<0.05; Fig.…”

Section: Expression Of Mir-26 In the Peripheral Blood Of Patients Witsupporting

confidence: 54%

Role of microRNA‑26a in the diagnosis of lower extremity deep vein thrombosis in patients with bone trauma

2017

Exp Ther Med

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Abstract. The present study aimed to investigate the role and mechanism of action of microRNA (miR)-26a in deep vein thrombosis (DVT). Peripheral blood was collected from 45 patients with DVT and 40 healthy controls. Levels of miR-26a, chemokine C-C motif ligand (CCL)2 mRNA and CCL7 mRNA were detected using reverse transcription-quantitative polymerase chain reaction and the value of miR-26a in the clinical diagnosis of DVT was assessed using receiver operating characteristic curve analysis. The correlation of miR-26a with CCL2 and CCL7 levels was analyzed using Spearman's rank correlation. In addition, miR-26a and protein kinase C δ (PRKCD) were overexpressed in human umbilical vein endothelial cells (HUVECs) and PRKCD expression was knocked down by small interfering (si)RNA. Western blotting was conducted to detect the expression of PRKCD and p65. Furthermore, a dual-luciferase reporter gene assay was performed. The results of the current study demonstrated that the expression of miR-26a was significantly downregulated in the peripheral blood of patients with DVT compared with healthy controls (P<0.05) and negatively correlated with CCL2 and CCL7 levels (P<0.05). Furthermore, it was demonstrated that miR-26a markedly inhibited the expression of PRKCD, significantly decreased levels of CCL2 and CCL7 mRNA (P<0.05) and inhibited activation of the NF-κB signaling pathway. Overexpression of PRKCD in HUVECs inhibited the effects of miR-26a and markedly upregulated the phosphorylation of p65. The present study indicated that miR-26a directly targets PRKCD mRNA and that miR-26a may be a useful biomarker in the clinical diagnosis of DVT. Thus, the present findings suggest that miR-26a regulates the NF-κB signaling pathway by binding to PRKCD mRNA, inhibits the expression of CCL2 and CCL7 and reduces the risk of DVT.

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Section: Expression Of Mir-26 In the Peripheral Blood Of Patients Witsupporting

confidence: 54%

Role of microRNA‑26a in the diagnosis of lower extremity deep vein thrombosis in patients with bone trauma

2017

Exp Ther Med

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“…This suggests that the bioavailability of leukocytes in the blood may be a major contributing factor that determines the number of leukocytes capable of reaching the CNS. This has previously been shown to be the case for inflammatory monocytes, where the number of monocytes migrating into the CNS was controlled primarily by how many had been mobilized into the blood (43,44). The enhanced pan-leukocyte infiltration into the CNS during WNV infection was reminiscent of the phenotype observed in the absence of IL-1␤ signaling, where WNV-infected Il-1r Ϫ/Ϫ mice also presented with a significant increase in leukocyte infiltration and overproduction of inflammatory cytokines in the CNS (45).…”

Section: Discussionmentioning

confidence: 87%

“…Titers of WNV were determined on Vero cell monolayers as previously described (43). Briefly, 150 l of virus-containing material was adsorbed for 1 h at 37°C in 24-well plates, and cells were overlaid with 1 ml of Opti-MEM (Invitrogen) supplemented with 0.8% methyl cellulose, 2% fetal bovine serum (FBS), and 50 g/ml gentamicin sulfate.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed with serial 6-m paraffin-embedded sections. After rehydration, antigen retrieval was performed using 10 mM citrate buffer at pH 6, as previously described (43). For monocyte/macrophage staining, slides were blocked for 1 h at room temperature and stained with rat anti-mouse MAC2 antibody (1:200; BioLegend) in Dako background reducing diluent.…”

Section: Methodsmentioning

confidence: 99%

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Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCEIn this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.KEYWORDS arbovirus, cell trafficking, chemokine receptors, chemokines, hostpathogen interactions, leukocytes, neuroimmunology, viral pathogenesis W est Nile virus (WNV) is a mosquito-transmitted flavivirus that was introduced into the United States in 1999 (1). Since then, the virus has spread rapidly across the continent and has become the leading cause of arthropod-borne virus-induced encephalitis in the United States. WNV is a significant public health concern due to the unpredictable nature of annual disease outbreaks and the lack of specific therapeutics and vaccines for human use (2). In humans, WNV is transmitted through the bite of an infected mosquito. The outcome of infection ranges from asymptomatic to severe neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis (3)(4)(5)

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“…Furthermore, our data also suggested that TNF-NAb decreased infiltration of blood iMo into the brains of infected mice by reducing their numbers in peripheral blood and not by directly decreasing the activation state of iMo in the brains of infected animals. Findings from previous studies in WNV encephalitis models have also argued that infiltration of iMo into the brains of WNV-infected mice was dependent on CCR2/CCL2 monocytosis in peripheral blood and not secondary to CCR2/CCL2-driven recruitment of iMo to the infected brain (73,86). It is also of interest that MCMV infection of adult mice results in Myd88-dependent mobilization and activation of monocytes in the bone marrow and that, in contrast to type I IFNs, IL-6, or IL-1, TNF-␣ appeared to potentially have a direct role in mobilization and activation of monocytes from the bone marrow (87).…”

Section: Discussionmentioning

confidence: 98%

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-␣)-neutralizing antibodies decreased the frequency of CD45 ϩ Ly6C hi CD11b ϩ CCR2 ϩ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMVinfected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-␣ is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-␣ plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-␣ normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.

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Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection

Cited by 80 publications

References 71 publications

Role of microRNA‑26a in the diagnosis of lower extremity deep vein thrombosis in patients with bone trauma

Role of microRNA‑26a in the diagnosis of lower extremity deep vein thrombosis in patients with bone trauma

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

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