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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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Requirement for MIP-1α in NK cell trafficking to liver. Mice deficient in MIP-1α, as a result of genetic mutation or treatment with antibodies neutralizing the factor, were used to evaluate effects on trafficking to virus-infected livers. Bone marrow leukocytes were harvested from untreated  mice, labeled with PKH26, and transferred intravenously into MCMV-infected recipients at 24 h after infection. Livers from recipient mice were harvested at 24 h after cell transfer. The following are shown: labeled cells from uninfected C57BL/6-RAG-1−/− mice transferred into infected C57BL/6-RAG-1−/− recipient mice either treated with control serum (A) or serum neutralizing MIP-1α (B) 1 d before infection, and labeled cells from uninfected  C57BL/6 mice transferred into infected C57BL/6 (C) or C57BL/6-MIP-1α−/− (D) recipient mice. Photographs were taken at ×31.25. Bar, 100 μm.  cv, central vein in A, for orientation. Large arrows point to foci with cell clusters. Small arrow points out individual sinusoidal cells.
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Figure 4: Requirement for MIP-1α in NK cell trafficking to liver. Mice deficient in MIP-1α, as a result of genetic mutation or treatment with antibodies neutralizing the factor, were used to evaluate effects on trafficking to virus-infected livers. Bone marrow leukocytes were harvested from untreated mice, labeled with PKH26, and transferred intravenously into MCMV-infected recipients at 24 h after infection. Livers from recipient mice were harvested at 24 h after cell transfer. The following are shown: labeled cells from uninfected C57BL/6-RAG-1−/− mice transferred into infected C57BL/6-RAG-1−/− recipient mice either treated with control serum (A) or serum neutralizing MIP-1α (B) 1 d before infection, and labeled cells from uninfected C57BL/6 mice transferred into infected C57BL/6 (C) or C57BL/6-MIP-1α−/− (D) recipient mice. Photographs were taken at ×31.25. Bar, 100 μm. cv, central vein in A, for orientation. Large arrows point to foci with cell clusters. Small arrow points out individual sinusoidal cells.

Mentions: To determine if the induced chemokine expression contributed to virus-induced recruitment of NK cells, cell trafficking experiments were carried out in mice lacking MIP-1α functions. For these studies, matched C57BL/6 and T and B cell–deficient C57BL/6-RAG-1−/− mice were used as donors and recipients. Recipients were MCMV infected for 24 h and either control treated or treated with antibodies neutralizing MIP-1α before infection. Livers were harvested at 24 h after cell transfer (Fig. 4, A and B; Table 4). Cell migration to sinusoidal cavities was MIP-1α independent, whereas the NK cell–dependent focal accumulation was MIP-1α dependent (Fig. 4 B, Table 4). Neutralization of MIP-1α in recipient mice inhibited the focal trafficking pattern by >75% (Table 4). As an independent and more complete evaluation of the role for MIP-1α, C57BL/6-MIP-1α−/− mice were examined. The focal, but not sinusoidal, trafficking pattern was inhibited by 100% in these mice (Table 4). Cell transfers from normal C56BL/6 donor to C57BL/6-MIP-1α−/− recipient mice, and C57BL/6-MIP-1α−/− donor to normal C56BL/6 recipient mice demonstrated that the requirement for MIP-1α was in recipient mice (Fig. 4, C and D; Table 4). Thus, there is a critical role for MIP-1α in promoting NK cell recruitment to liver during MCMV infection.


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)

Requirement for MIP-1α in NK cell trafficking to liver. Mice deficient in MIP-1α, as a result of genetic mutation or treatment with antibodies neutralizing the factor, were used to evaluate effects on trafficking to virus-infected livers. Bone marrow leukocytes were harvested from untreated  mice, labeled with PKH26, and transferred intravenously into MCMV-infected recipients at 24 h after infection. Livers from recipient mice were harvested at 24 h after cell transfer. The following are shown: labeled cells from uninfected C57BL/6-RAG-1−/− mice transferred into infected C57BL/6-RAG-1−/− recipient mice either treated with control serum (A) or serum neutralizing MIP-1α (B) 1 d before infection, and labeled cells from uninfected  C57BL/6 mice transferred into infected C57BL/6 (C) or C57BL/6-MIP-1α−/− (D) recipient mice. Photographs were taken at ×31.25. Bar, 100 μm.  cv, central vein in A, for orientation. Large arrows point to foci with cell clusters. Small arrow points out individual sinusoidal cells.
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Related In: Results  -  Collection

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Figure 4: Requirement for MIP-1α in NK cell trafficking to liver. Mice deficient in MIP-1α, as a result of genetic mutation or treatment with antibodies neutralizing the factor, were used to evaluate effects on trafficking to virus-infected livers. Bone marrow leukocytes were harvested from untreated mice, labeled with PKH26, and transferred intravenously into MCMV-infected recipients at 24 h after infection. Livers from recipient mice were harvested at 24 h after cell transfer. The following are shown: labeled cells from uninfected C57BL/6-RAG-1−/− mice transferred into infected C57BL/6-RAG-1−/− recipient mice either treated with control serum (A) or serum neutralizing MIP-1α (B) 1 d before infection, and labeled cells from uninfected C57BL/6 mice transferred into infected C57BL/6 (C) or C57BL/6-MIP-1α−/− (D) recipient mice. Photographs were taken at ×31.25. Bar, 100 μm. cv, central vein in A, for orientation. Large arrows point to foci with cell clusters. Small arrow points out individual sinusoidal cells.
Mentions: To determine if the induced chemokine expression contributed to virus-induced recruitment of NK cells, cell trafficking experiments were carried out in mice lacking MIP-1α functions. For these studies, matched C57BL/6 and T and B cell–deficient C57BL/6-RAG-1−/− mice were used as donors and recipients. Recipients were MCMV infected for 24 h and either control treated or treated with antibodies neutralizing MIP-1α before infection. Livers were harvested at 24 h after cell transfer (Fig. 4, A and B; Table 4). Cell migration to sinusoidal cavities was MIP-1α independent, whereas the NK cell–dependent focal accumulation was MIP-1α dependent (Fig. 4 B, Table 4). Neutralization of MIP-1α in recipient mice inhibited the focal trafficking pattern by >75% (Table 4). As an independent and more complete evaluation of the role for MIP-1α, C57BL/6-MIP-1α−/− mice were examined. The focal, but not sinusoidal, trafficking pattern was inhibited by 100% in these mice (Table 4). Cell transfers from normal C56BL/6 donor to C57BL/6-MIP-1α−/− recipient mice, and C57BL/6-MIP-1α−/− donor to normal C56BL/6 recipient mice demonstrated that the requirement for MIP-1α was in recipient mice (Fig. 4, C and D; Table 4). Thus, there is a critical role for MIP-1α in promoting NK cell recruitment to liver during MCMV infection.

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