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Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Salazar-Mather TP, Orange JS, Biron CA - J. Exp. Med. (1998)

Bottom Line: Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses.NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers.The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

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Characterization of liver inflammatory foci during MCMV infections. Livers were harvested and tissue sections prepared from uninfected  mice (A) or day 2 MCMV-infected mice (B–F) as described in Materials and Methods. All panels present areas encompassing a central vein. (cv, central  vein, given in A for orientation). A–C show morphology of H&E–stained paraffin sections from (A) uninfected C57BL/6, (B) day 2 infected C57BL/6,  (C) and day 2 infected C57BL/6-SCID. Large arrows in B and C denote inflammatory areas presented in insets. D–F show immunohistochemically  stained frozen sections from day 2 MCMV-infected C57BL/6-SCID mice, localizing viral antigen expression relative to NK cells, monocyte/macrophages,  or IFN-γ protein. MCMV antigen expression is detected by staining of infected cells with brown precipitate and tissues are counterstained with methyl  green in all three panels. Staining of second antigens as dark blue precipitates are as follows: (D) AGM1 staining of NK cells, (E) F4/80 staining of monocyte/  macrophage populations, and (F) IFN-γ protein staining. Panel photographs were taken at ×31.25. Inset photographs were taken at ×125. Bars, 100 μm.
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Figure 1: Characterization of liver inflammatory foci during MCMV infections. Livers were harvested and tissue sections prepared from uninfected mice (A) or day 2 MCMV-infected mice (B–F) as described in Materials and Methods. All panels present areas encompassing a central vein. (cv, central vein, given in A for orientation). A–C show morphology of H&E–stained paraffin sections from (A) uninfected C57BL/6, (B) day 2 infected C57BL/6, (C) and day 2 infected C57BL/6-SCID. Large arrows in B and C denote inflammatory areas presented in insets. D–F show immunohistochemically stained frozen sections from day 2 MCMV-infected C57BL/6-SCID mice, localizing viral antigen expression relative to NK cells, monocyte/macrophages, or IFN-γ protein. MCMV antigen expression is detected by staining of infected cells with brown precipitate and tissues are counterstained with methyl green in all three panels. Staining of second antigens as dark blue precipitates are as follows: (D) AGM1 staining of NK cells, (E) F4/80 staining of monocyte/ macrophage populations, and (F) IFN-γ protein staining. Panel photographs were taken at ×31.25. Inset photographs were taken at ×125. Bars, 100 μm.

Mentions: Previous studies have shown that focal liver inflammation peaks at 2–3 d after intraperitoneal infection with MCMV (15, 19, 24). To characterize the cellular compositions of, and contributions to, these responses, samples were isolated from uninfected mice or mice infected with MCMV at times of peak inflammatory responses. Normal and specific lymphocyte subset-deficient mice were examined. Tissue sections were prepared and H&E stained for morphological analyses. In contrast to control uninfected livers (Fig. 1 A), day 2 MCMV-infected livers from normal C57BL/6 mice had four to six infiltrate clusters per lobular region, each with ⩾6 nucleated cells, localized between portal areas and central veins (Fig. 1 B). MCMV-induced intranuclear inclusions, termed cytomegalic inclusion bodies, were occasionally seen associated with inflammatory foci. To evaluate contributions of T and/or B cells to early inflammatory foci development, responses in T and B cell–deficient C57BL/6-SCID, T and B cell–deficient C57BL/6-RAG-1−/−, and T cell–deficient C57BL/6-nude mice were examined (Fig. 1 and Table 1). Foci were not observed in uninfected samples from any, but were observed in high frequencies in day 2 MCMV-infected livers from all, of these mouse strains. Thus, development of liver inflammation during early MCMV infection did not require presence of either T or B cells.


Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Salazar-Mather TP, Orange JS, Biron CA - J. Exp. Med. (1998)

Characterization of liver inflammatory foci during MCMV infections. Livers were harvested and tissue sections prepared from uninfected  mice (A) or day 2 MCMV-infected mice (B–F) as described in Materials and Methods. All panels present areas encompassing a central vein. (cv, central  vein, given in A for orientation). A–C show morphology of H&E–stained paraffin sections from (A) uninfected C57BL/6, (B) day 2 infected C57BL/6,  (C) and day 2 infected C57BL/6-SCID. Large arrows in B and C denote inflammatory areas presented in insets. D–F show immunohistochemically  stained frozen sections from day 2 MCMV-infected C57BL/6-SCID mice, localizing viral antigen expression relative to NK cells, monocyte/macrophages,  or IFN-γ protein. MCMV antigen expression is detected by staining of infected cells with brown precipitate and tissues are counterstained with methyl  green in all three panels. Staining of second antigens as dark blue precipitates are as follows: (D) AGM1 staining of NK cells, (E) F4/80 staining of monocyte/  macrophage populations, and (F) IFN-γ protein staining. Panel photographs were taken at ×31.25. Inset photographs were taken at ×125. Bars, 100 μm.
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Related In: Results  -  Collection

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Figure 1: Characterization of liver inflammatory foci during MCMV infections. Livers were harvested and tissue sections prepared from uninfected mice (A) or day 2 MCMV-infected mice (B–F) as described in Materials and Methods. All panels present areas encompassing a central vein. (cv, central vein, given in A for orientation). A–C show morphology of H&E–stained paraffin sections from (A) uninfected C57BL/6, (B) day 2 infected C57BL/6, (C) and day 2 infected C57BL/6-SCID. Large arrows in B and C denote inflammatory areas presented in insets. D–F show immunohistochemically stained frozen sections from day 2 MCMV-infected C57BL/6-SCID mice, localizing viral antigen expression relative to NK cells, monocyte/macrophages, or IFN-γ protein. MCMV antigen expression is detected by staining of infected cells with brown precipitate and tissues are counterstained with methyl green in all three panels. Staining of second antigens as dark blue precipitates are as follows: (D) AGM1 staining of NK cells, (E) F4/80 staining of monocyte/ macrophage populations, and (F) IFN-γ protein staining. Panel photographs were taken at ×31.25. Inset photographs were taken at ×125. Bars, 100 μm.
Mentions: Previous studies have shown that focal liver inflammation peaks at 2–3 d after intraperitoneal infection with MCMV (15, 19, 24). To characterize the cellular compositions of, and contributions to, these responses, samples were isolated from uninfected mice or mice infected with MCMV at times of peak inflammatory responses. Normal and specific lymphocyte subset-deficient mice were examined. Tissue sections were prepared and H&E stained for morphological analyses. In contrast to control uninfected livers (Fig. 1 A), day 2 MCMV-infected livers from normal C57BL/6 mice had four to six infiltrate clusters per lobular region, each with ⩾6 nucleated cells, localized between portal areas and central veins (Fig. 1 B). MCMV-induced intranuclear inclusions, termed cytomegalic inclusion bodies, were occasionally seen associated with inflammatory foci. To evaluate contributions of T and/or B cells to early inflammatory foci development, responses in T and B cell–deficient C57BL/6-SCID, T and B cell–deficient C57BL/6-RAG-1−/−, and T cell–deficient C57BL/6-nude mice were examined (Fig. 1 and Table 1). Foci were not observed in uninfected samples from any, but were observed in high frequencies in day 2 MCMV-infected livers from all, of these mouse strains. Thus, development of liver inflammation during early MCMV infection did not require presence of either T or B cells.

Bottom Line: Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses.NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers.The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.

ABSTRACT
Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

Show MeSH
Related in: MedlinePlus