title: Mast cells play a key role in host defense against herpes simplex virus infection through TNF-α and IL-6 production.
abstract: The essential contribution of mast cells (MCs) to bacterial host defense has been well established; however, little is known about their role in viral infections in vivo. Here, we found that intradermal injection with herpes simplex virus 2 (HSV-2) into MC-deficient Kit(W/Wv) mice led to increased clinical severity and mortality with elevated virus titers in HSV-infected skins. Ex vivo HSV-specific tetramer staining assay demonstrated that MC deficiency did not affect the frequency of HSV-specific cytotoxic T lymphocytes (CTLs) in draining lymph nodes. Moreover, the high mortality in Kit(W/W-v) mice was completely reversed by intradermal reconstitution with bone marrow-derived MCs (BMMCs) from wild-type, but not TNF(-/-) or IL-6(-/-) mice, indicating that MCs or, more specifically, MC-derived tumor necrosis factor (TNF) and IL-6 can protect mice from HSV-induced mortality. However, HSV did not directly induce TNF-α or IL-6 production by BMMCs; supernatants from HSV-infected keratinocytes induced the production of these cytokines by BMMCs without degranulation. Furthermore, IL-33 expression was induced in HSV-infected keratinocytes, and blocking the IL-33 receptor T1/ST2 on BMMCs significantly reduced TNF-α and IL-6 production by BMMCs. These results indicate the involvement of MCs in host defense at HSV-infected sites through TNF-α and IL-6 production, which is induced by keratinocyte-derived IL-33.
authors.affiliation: Department of Dermatology, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Aoki
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.forename: Youichi
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimada
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002522:Chlorocebus aethiops; D003872:Dermatitis / Q000276:immunology / Q000401:mortality / Q000821:virology; D005260:Female; D055879:Gene Knock-In Techniques; D006561:Herpes Simplex / Q000276:immunology* / Q000401:mortality; D018258:Herpesvirus 2, Human / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014709:Vero Cells
chemical_list: C506535:Il33 protein, mouse; D016898:Interferon-alpha; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha