Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection

Stock, Angus T.; Smith, Jeffrey M.; Carbone, Federico

doi:10.1084/jem.20132183

Cited by 49 publications

(54 citation statements)

References 24 publications

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“…Patterns in TG-infiltrating CD11b + myeloid cells produced several noteworthy observations but were not associated with the susceptibility of STING −/− mice. Consistent with the reported repressive role of IFNα/β signaling (52), neutrophil infiltration was limited in TG from STING −/− mice (Fig. 6 E) despite a high viral burden (Fig.…”

Section: Resultssupporting

confidence: 89%

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Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways

Royer

Conrady

Carr

2016

The Journal of Immunology

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Type I interferon (IFNα/β)-driven immune responses to acute viral infection are critical to counter replication and prevent dissemination. However, the mechanisms underlying host resistance to herpes simplex virus type 1 (HSV-1) are incompletely understood. Here we show that mice with deficiencies in IFNα/β signaling or STING exhibit exacerbated neurovirulence and atypical lymphotropic dissemination of HSV-1 following ocular infection. Synergy between IFNα/β signaling and efficacy of early adaptive immune responses to HSV-1 were dissected using bone marrow chimeras and adoptive cell transfer approaches to profile clonal expansion, effector function, and recruitment of HSV-specific CD8+ T cells. Lymphotropic viral dissemination was commensurate with abrogated CD8+ T cell responses and pathological alterations of fibroblastic reticular cell (FRC) networks in the draining lymph nodes. Our results show that resistance to HSV-1 in the TG during acute infection is conferred in part by STING and IFNα/β-signaling in both bone marrow-derived and resident cells, which coalesce to support a robust HSV-1-specific CD8+ T cell response.

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Section: Resultssupporting

confidence: 89%

“…6, F and G). Distinct anatomical host niches differ in profiles of neutrophil recruitment and monocyte differentiation during inflammation and infection, as indicated above comparing cellular innate responses in nervous and mucosal tissue and validated by others (52, 55, 56). …”

Section: Resultssupporting

confidence: 70%

Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways

Royer

Conrady

Carr

2016

The Journal of Immunology

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“…IL-6 released from SGCs and neurons will likely affect nearby neurons or SGCs within TG (Brazda et al, 2013). Under injury condition, CXCL2 expressed by monocytes aids neutrophil recruitment into the ganglia (Stock et al, 2014). There is evidence that CXCL2 contributes to pathological pain conditions by aggravating peripheral and spinal pronociceptive inflammatory responses and that TRPM2 is required for CXCL2 expression under injury or inflammatory condition (Haraguchi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia

Chung¹,

Asgar²,

Lee³

et al. 2015

Neuroscience

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Trigeminal ganglia (TG) contain neuronal cell bodies surrounded by satellite glial cells. Although peripheral injury is well known to induce changes in gene expression within sensory ganglia, detailed mechanisms whereby peripheral injury leads to gene expression within sensory ganglia are not completely understood. Reactive oxygen species (ROS) are an important modulator of hyperalgesia, but the role of ROS generated within sensory ganglia is unclear. Since ROS are known to affect transcription processes, ROS generated within sensory ganglia could directly influence gene expression and induce cellular changes at the soma level. In this study, we hypothesized that peripheral inflammation leads to cytokine and chemokine production and ROS generation within TG and that transient receptor potential melastatin (TRPM2), a well known oxidative sensor, contributes to ROS-induced gene regulation within TG. The masseter injection of complete Freund’s adjuvant (CFA) resulted in a significantly elevated level of ROS within TG of the inflamed side with a concurrent increase in cytokine expression in TG. Treatment of TG cultures with H2O2 significantly up-regulated mRNA and protein levels of cytokine/chemokine such as interleukin 6 (IL-6) and chemokine (C-X-C motif) ligand 2 (CXCL2). TRPM2 was expressed in both neurons and nonneuronal cells in TG, and pretreatment of TG cultures with 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of TRPM2, or siRNA against TRPM2 attenuated H2O2-induced up-regulation of IL-6 and CXCL2. These results suggested that activation of TRPM2 could play an important role in the modulation of cytokine/chemokine expression within TG under oxidative stress and that such changes may contribute to amplification of nociceptive signals leading to pathological pain conditions.

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“…However, during skin infection, various chemokines are induced (Stock et al, 2014), which could contribute to directed T cell migration toward viral pathogens. To test whether the abnormal morphology of Dock8-deficient T cells was associated with impaired chemotaxis, we tracked individual cells moving through collagen matrices toward a gradient of CXCL12 (SDF-1).…”

Section: Dock8-deficient T Cells and Nk Cells Develop Abnormally Elonmentioning

confidence: 99%

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

Zhang¹,

Dove²,

Hor³

et al. 2014

J Cell Biol

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DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.

show abstract

Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection

Abstract: Type I IFN directly and selectively suppresses Cxcl2 expression by monocytes, and abrogates their ability to recruit neutrophils to the sensory ganglia following HSV-1 infection.

Cited by 49 publications

References 24 publications

Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways

Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNα/β Defense Pathways

The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

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