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Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.

Seo SU, Kwon HJ, Ko HJ, Byun YH, Seong BL, Uematsu S, Akira S, Kweon MN - PLoS Pathog. (2011)

Bottom Line: Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation.Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes.In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunology Section, International Vaccine Institute, Seoul, South Korea.

ABSTRACT
Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation. IFN-I receptor knockout (Ifnar1⁻/⁻) mice develop significant defects in the infiltration of Ly6C(hi) monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6C(hi) monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6C(int) monocytes of Ifnar1⁻/⁻ mice mainly produce KC for neutrophil influx. As a consequence, Ifnar1⁻/⁻ mice recruit more neutrophils after influenza infection than do WT mice. Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes. By using BM chimeric mice (WT BM into Ifnar1⁻/⁻ and vice versa), we confirmed that IFN-I signaling in hematopoietic cells is required for the generation of Ly6C(hi) monocytes. Of note, WT BM reconstituted Ifnar1⁻/⁻ chimeric mice with increased numbers of Ly6C(hi) monocytes survived longer than influenza-infected Ifnar1⁻/⁻ mice. In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells. Collectively, these data suggest that IFN-I contributes to resistance of influenza infection by control of monocytes and neutrophils in the lung.

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Monocytes of Ifnar1−/− mice express different patterns of genes.WT and Ifnar1−/− mice were infected i.n. with 1×105 pfu PR8 and monocytes were sorted. Total RNA was extracted and gene expression profiles were analyzed on gene chip. Data are representative of two independent experiments.
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ppat-1001304-g004: Monocytes of Ifnar1−/− mice express different patterns of genes.WT and Ifnar1−/− mice were infected i.n. with 1×105 pfu PR8 and monocytes were sorted. Total RNA was extracted and gene expression profiles were analyzed on gene chip. Data are representative of two independent experiments.

Mentions: For macroscopic comparison between monocytes recruited in the lung of influenza-infected WT and Ifnar1−/− mice, we performed gene chip analysis (Figure 4). As expected, IFN-I-regulated genes (e.g., Mx, Oas, Irf, etc.) were significantly decreased in monocytes isolated from Ifnar1−/− mice. Of the genes elevated in Ly6Cint monocytes isolated from Ifnar1−/− mice, S100a8/S100a9 and Trem1 are associated with inflammatory responses in various diseases [32], [33]. In contrast, negative regulators of inflammation, Trim21 and Trim30 [34], [35], were up-regulated in Ly6Chi monocytes isolated from WT mice when compared to Ly6Cint monocytes from Ifnar1−/− mice. These inflammation-biased gene expressions by Ly6Cint monocytes may explain the higher susceptibility of Ifnar1−/− mice to influenza infection. Ly6Chi monocytes from WT mice were also superior in expressing genes involved in lipid metabolism (e.g., Apoe, Apoc2, etc.). Interestingly, the 1918 pandemic influenza virus was found to block lipid metabolism as part of its evasion strategy against antiviral responses [36]. Furthermore, influenza infection causes prominent inflammation in Apoe−/− mice [37], indicating that a defect in lipid metabolism in Ifnar1−/− mice might contribute to worsen inflammation. Collectively, we confirmed that monocytes from WT and Ifnar1−/− mice have significantly different characteristics and that lack of IFN-I signaling changes gene expression bias to augment inflammation.


Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.

Seo SU, Kwon HJ, Ko HJ, Byun YH, Seong BL, Uematsu S, Akira S, Kweon MN - PLoS Pathog. (2011)

Monocytes of Ifnar1−/− mice express different patterns of genes.WT and Ifnar1−/− mice were infected i.n. with 1×105 pfu PR8 and monocytes were sorted. Total RNA was extracted and gene expression profiles were analyzed on gene chip. Data are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044702&req=5

ppat-1001304-g004: Monocytes of Ifnar1−/− mice express different patterns of genes.WT and Ifnar1−/− mice were infected i.n. with 1×105 pfu PR8 and monocytes were sorted. Total RNA was extracted and gene expression profiles were analyzed on gene chip. Data are representative of two independent experiments.
Mentions: For macroscopic comparison between monocytes recruited in the lung of influenza-infected WT and Ifnar1−/− mice, we performed gene chip analysis (Figure 4). As expected, IFN-I-regulated genes (e.g., Mx, Oas, Irf, etc.) were significantly decreased in monocytes isolated from Ifnar1−/− mice. Of the genes elevated in Ly6Cint monocytes isolated from Ifnar1−/− mice, S100a8/S100a9 and Trem1 are associated with inflammatory responses in various diseases [32], [33]. In contrast, negative regulators of inflammation, Trim21 and Trim30 [34], [35], were up-regulated in Ly6Chi monocytes isolated from WT mice when compared to Ly6Cint monocytes from Ifnar1−/− mice. These inflammation-biased gene expressions by Ly6Cint monocytes may explain the higher susceptibility of Ifnar1−/− mice to influenza infection. Ly6Chi monocytes from WT mice were also superior in expressing genes involved in lipid metabolism (e.g., Apoe, Apoc2, etc.). Interestingly, the 1918 pandemic influenza virus was found to block lipid metabolism as part of its evasion strategy against antiviral responses [36]. Furthermore, influenza infection causes prominent inflammation in Apoe−/− mice [37], indicating that a defect in lipid metabolism in Ifnar1−/− mice might contribute to worsen inflammation. Collectively, we confirmed that monocytes from WT and Ifnar1−/− mice have significantly different characteristics and that lack of IFN-I signaling changes gene expression bias to augment inflammation.

Bottom Line: Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation.Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes.In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunology Section, International Vaccine Institute, Seoul, South Korea.

ABSTRACT
Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation. IFN-I receptor knockout (Ifnar1⁻/⁻) mice develop significant defects in the infiltration of Ly6C(hi) monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6C(hi) monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6C(int) monocytes of Ifnar1⁻/⁻ mice mainly produce KC for neutrophil influx. As a consequence, Ifnar1⁻/⁻ mice recruit more neutrophils after influenza infection than do WT mice. Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes. By using BM chimeric mice (WT BM into Ifnar1⁻/⁻ and vice versa), we confirmed that IFN-I signaling in hematopoietic cells is required for the generation of Ly6C(hi) monocytes. Of note, WT BM reconstituted Ifnar1⁻/⁻ chimeric mice with increased numbers of Ly6C(hi) monocytes survived longer than influenza-infected Ifnar1⁻/⁻ mice. In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells. Collectively, these data suggest that IFN-I contributes to resistance of influenza infection by control of monocytes and neutrophils in the lung.

Show MeSH
Related in: MedlinePlus