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Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.

Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, Culley FJ, Mack M, Akira S, Johansson C - J. Exp. Med. (2015)

Bottom Line: AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV.Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity.Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.

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Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.

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MAVS-dependent recruitment of TNF-producing CD64hi inflammatory cells to RSV-infected lungs. (A) Representative plots of CD11bhiCD64hi inflammatory cells in the lungs of mock (PBS)- or RSV-infected WT or Mavs−/− mice 18 h p.i. with RSV. (B) Quantification of CD64hi inflammatory cells in the lungs of WT and Mavs−/− mice during infection. Data are mean ± SEM of four to five mice per group. (C) Representative plots of Ly6C and CD11c expression on CD64hiCD11bhi inflammatory cells (gated as in Fig. S1 A) at the indicated time points after RSV infection of WT mice. (D) Representative histograms of Ly6C expression on CD64hi inflammatory cells at the indicated time points p.i. of WT mice. (E) Quantification of the total number of CD64hi cells split into CD11chi (moDCs; black) or CD11clo (infMos; gray) at the indicated time points p.i. of WT mice. Data are mean ± SEM of five mice per group. (F) Number of TNF-positive CD64hiCD11chi moDCs in the lungs of WT or Mavs−/− mice at the indicated time points p.i. 0 h represents mock (PBS)-infected mice. Expression was determined by intracellular staining for TNF and flow cytometry analysis. Data are mean ± SEM of five mice per group. (G) Ex vivo production of TNF secreted into culture supernatants by total lung cells and FACS-sorted CD64hiCD11chi moDCs isolated from WT mice at 18 h p.i. Each point represents one individual experiment using cells pooled from 25–40 mice. In A–F, the data are representative of at least two independent experiments. Statistical significance of differences between WT and Mavs−/− mice at different time points was determined by unpaired Student’s t test. **, P < 0.01; ***, P < 0.001.
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fig5: MAVS-dependent recruitment of TNF-producing CD64hi inflammatory cells to RSV-infected lungs. (A) Representative plots of CD11bhiCD64hi inflammatory cells in the lungs of mock (PBS)- or RSV-infected WT or Mavs−/− mice 18 h p.i. with RSV. (B) Quantification of CD64hi inflammatory cells in the lungs of WT and Mavs−/− mice during infection. Data are mean ± SEM of four to five mice per group. (C) Representative plots of Ly6C and CD11c expression on CD64hiCD11bhi inflammatory cells (gated as in Fig. S1 A) at the indicated time points after RSV infection of WT mice. (D) Representative histograms of Ly6C expression on CD64hi inflammatory cells at the indicated time points p.i. of WT mice. (E) Quantification of the total number of CD64hi cells split into CD11chi (moDCs; black) or CD11clo (infMos; gray) at the indicated time points p.i. of WT mice. Data are mean ± SEM of five mice per group. (F) Number of TNF-positive CD64hiCD11chi moDCs in the lungs of WT or Mavs−/− mice at the indicated time points p.i. 0 h represents mock (PBS)-infected mice. Expression was determined by intracellular staining for TNF and flow cytometry analysis. Data are mean ± SEM of five mice per group. (G) Ex vivo production of TNF secreted into culture supernatants by total lung cells and FACS-sorted CD64hiCD11chi moDCs isolated from WT mice at 18 h p.i. Each point represents one individual experiment using cells pooled from 25–40 mice. In A–F, the data are representative of at least two independent experiments. Statistical significance of differences between WT and Mavs−/− mice at different time points was determined by unpaired Student’s t test. **, P < 0.01; ***, P < 0.001.

Mentions: We further determined the effect of RSV infection on inflammatory cell recruitment to the lungs and extravasation into the airways. The recruitment of polymorphonuclear phagocytes, which occurs early after infection, was largely independent of MAVS as similar proportions and numbers of neutrophils were present in bronchoalveolar lavages (BALs; a representation of the airways) and lung cell suspensions from infected MAVS-sufficient and -deficient mice (Fig. 4, D and E). Consistent with this notion, substantial expression of the neutrophil chemoattractant Cxcl1 was detected early after infection in both WT and Mavs−/− mice even though levels were higher in the former group (Fig. 4 F). Similarly, Cxcl1 induction and unimpaired neutrophil recruitment was also observed in IFNAR1-deficient mice infected with RSV (Goritzka et al., 2014). The recruitment of T cells, including RSV-specific CD8+ T cells, detected at day 8 p.i., also did not differ between WT and Mavs−/− mice (Fig. 4, G–I; Bhoj et al., 2008; Demoor et al., 2012). In contrast, we noticed a large difference between WT and Mavs−/− mice in lung accumulation of CD64hi inflammatory cells after RSV infection. In WT mice, leukocytes positive for CD64 and CD11b represented ∼40% of the total leukocyte population at day 2 p.i., but those cells were completely absent in lungs of Mavs−/− mice at all time points (Fig. 5, A and B). Thus, MAVS deficiency results in a general impairment of inflammatory cytokine production and absence of CD64hi inflammatory cells in the lungs after RSV infection, but does not impact neutrophil or T cell recruitment.


Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.

Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, Culley FJ, Mack M, Akira S, Johansson C - J. Exp. Med. (2015)

MAVS-dependent recruitment of TNF-producing CD64hi inflammatory cells to RSV-infected lungs. (A) Representative plots of CD11bhiCD64hi inflammatory cells in the lungs of mock (PBS)- or RSV-infected WT or Mavs−/− mice 18 h p.i. with RSV. (B) Quantification of CD64hi inflammatory cells in the lungs of WT and Mavs−/− mice during infection. Data are mean ± SEM of four to five mice per group. (C) Representative plots of Ly6C and CD11c expression on CD64hiCD11bhi inflammatory cells (gated as in Fig. S1 A) at the indicated time points after RSV infection of WT mice. (D) Representative histograms of Ly6C expression on CD64hi inflammatory cells at the indicated time points p.i. of WT mice. (E) Quantification of the total number of CD64hi cells split into CD11chi (moDCs; black) or CD11clo (infMos; gray) at the indicated time points p.i. of WT mice. Data are mean ± SEM of five mice per group. (F) Number of TNF-positive CD64hiCD11chi moDCs in the lungs of WT or Mavs−/− mice at the indicated time points p.i. 0 h represents mock (PBS)-infected mice. Expression was determined by intracellular staining for TNF and flow cytometry analysis. Data are mean ± SEM of five mice per group. (G) Ex vivo production of TNF secreted into culture supernatants by total lung cells and FACS-sorted CD64hiCD11chi moDCs isolated from WT mice at 18 h p.i. Each point represents one individual experiment using cells pooled from 25–40 mice. In A–F, the data are representative of at least two independent experiments. Statistical significance of differences between WT and Mavs−/− mice at different time points was determined by unpaired Student’s t test. **, P < 0.01; ***, P < 0.001.
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fig5: MAVS-dependent recruitment of TNF-producing CD64hi inflammatory cells to RSV-infected lungs. (A) Representative plots of CD11bhiCD64hi inflammatory cells in the lungs of mock (PBS)- or RSV-infected WT or Mavs−/− mice 18 h p.i. with RSV. (B) Quantification of CD64hi inflammatory cells in the lungs of WT and Mavs−/− mice during infection. Data are mean ± SEM of four to five mice per group. (C) Representative plots of Ly6C and CD11c expression on CD64hiCD11bhi inflammatory cells (gated as in Fig. S1 A) at the indicated time points after RSV infection of WT mice. (D) Representative histograms of Ly6C expression on CD64hi inflammatory cells at the indicated time points p.i. of WT mice. (E) Quantification of the total number of CD64hi cells split into CD11chi (moDCs; black) or CD11clo (infMos; gray) at the indicated time points p.i. of WT mice. Data are mean ± SEM of five mice per group. (F) Number of TNF-positive CD64hiCD11chi moDCs in the lungs of WT or Mavs−/− mice at the indicated time points p.i. 0 h represents mock (PBS)-infected mice. Expression was determined by intracellular staining for TNF and flow cytometry analysis. Data are mean ± SEM of five mice per group. (G) Ex vivo production of TNF secreted into culture supernatants by total lung cells and FACS-sorted CD64hiCD11chi moDCs isolated from WT mice at 18 h p.i. Each point represents one individual experiment using cells pooled from 25–40 mice. In A–F, the data are representative of at least two independent experiments. Statistical significance of differences between WT and Mavs−/− mice at different time points was determined by unpaired Student’s t test. **, P < 0.01; ***, P < 0.001.
Mentions: We further determined the effect of RSV infection on inflammatory cell recruitment to the lungs and extravasation into the airways. The recruitment of polymorphonuclear phagocytes, which occurs early after infection, was largely independent of MAVS as similar proportions and numbers of neutrophils were present in bronchoalveolar lavages (BALs; a representation of the airways) and lung cell suspensions from infected MAVS-sufficient and -deficient mice (Fig. 4, D and E). Consistent with this notion, substantial expression of the neutrophil chemoattractant Cxcl1 was detected early after infection in both WT and Mavs−/− mice even though levels were higher in the former group (Fig. 4 F). Similarly, Cxcl1 induction and unimpaired neutrophil recruitment was also observed in IFNAR1-deficient mice infected with RSV (Goritzka et al., 2014). The recruitment of T cells, including RSV-specific CD8+ T cells, detected at day 8 p.i., also did not differ between WT and Mavs−/− mice (Fig. 4, G–I; Bhoj et al., 2008; Demoor et al., 2012). In contrast, we noticed a large difference between WT and Mavs−/− mice in lung accumulation of CD64hi inflammatory cells after RSV infection. In WT mice, leukocytes positive for CD64 and CD11b represented ∼40% of the total leukocyte population at day 2 p.i., but those cells were completely absent in lungs of Mavs−/− mice at all time points (Fig. 5, A and B). Thus, MAVS deficiency results in a general impairment of inflammatory cytokine production and absence of CD64hi inflammatory cells in the lungs after RSV infection, but does not impact neutrophil or T cell recruitment.

Bottom Line: AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV.Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity.Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.

Show MeSH
Related in: MedlinePlus