Limits...
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.

Show MeSH

Related in: MedlinePlus

Ifnar1−/− mice are more susceptible to influenza infection than wild-type (WT) mice.(A) Survival and weight loss of WT and Ifnar1−/− mice after intranasal (i.n.) infection with 1×105 pfu or 2×104 pfu PR8 virus. (B) Viral load was measured by plaque assay in the lung of mice infected with 1×105 pfu PR8 virus at 2 (n = 6) and 5 (n = 11) days post infection (dpi). Total protein (C) and cytokine (D) levels were determined in the BALF of PR8-infected mice at 3 and 5 dpi. (C, D) Values are mean + SD and results are representative of three independent experiments with n>5 for each group. Histopathological scores (E) and representative photos (F) of lungs from WT and Ifnar1−/− mice (3 mice/group) after infection with 1×105 pfu PR8 virus and staining with H&E or MPO. Bars: 100 µm or 25 µm (enlarged pictures).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3044702&req=5

ppat-1001304-g001: Ifnar1−/− mice are more susceptible to influenza infection than wild-type (WT) mice.(A) Survival and weight loss of WT and Ifnar1−/− mice after intranasal (i.n.) infection with 1×105 pfu or 2×104 pfu PR8 virus. (B) Viral load was measured by plaque assay in the lung of mice infected with 1×105 pfu PR8 virus at 2 (n = 6) and 5 (n = 11) days post infection (dpi). Total protein (C) and cytokine (D) levels were determined in the BALF of PR8-infected mice at 3 and 5 dpi. (C, D) Values are mean + SD and results are representative of three independent experiments with n>5 for each group. Histopathological scores (E) and representative photos (F) of lungs from WT and Ifnar1−/− mice (3 mice/group) after infection with 1×105 pfu PR8 virus and staining with H&E or MPO. Bars: 100 µm or 25 µm (enlarged pictures).

Mentions: Because many previous studies indicate a crucial role for IFN-I in host defense against influenza infection, we looked for crucial regulatory factors that are mainly regulated by IFN-I after influenza infection using Ifnar1−/− mice of B6 background. First we challenged Ifnar1−/− and WT mice with a lethal dose (1×105 pfu) of PR8 virus. The Ifnar1−/− mice started to die 5 days post infection (dpi) and all were dead within 8 dpi while approximately 50% of WT mice survived (Figure 1A). When we decreased the challenge dose of PR8 virus (2×104 pfu), virus infection killed Ifnar1−/− mice from 5 dpi and no mice survived at 13 dpi while 80% of WT B6 mice survived (Figure 1A). WT mice started to regain body weight 8 or 9 days after infection while Ifnar1−/− mice continued to lose weight until they died (Figure 1A). Since the contribution of IFN-I in viral clearance is controversial [22], [23], we next addressed viral titer in the lung at 2 and 5 dpi with influenza PR8 virus (1×105 pfu). Intriguingly, Ifnar1−/− mice showed higher viral titer in the lung than WT mice at 2 dpi but not at 5 dpi (Figure 1B). However, total protein levels were significantly higher in the bronchoalveolar lavage fluid (BALF) of Ifnar1−/− mice at 5 dpi than in WT mice (Figure 1C). Of note, significant levels of IL-6, TNF-α and IP-10 were determined at 3 dpi in the BALF of Ifnar1−/− mice and high levels IFN-γ and IL-6 at 5 dpi when compared with levels in WT mice (Figure 1D). Lung histopathology of WT and Ifnar1−/− mice after H&E staining revealed more edema, alveolar hemorrhage, alveolar wall thickness, and neutrophil infiltration in Ifnar1−/− mice than in WT mice at 5 dpi (Figure 1E and 1F). Staining specifically for myeloperoxidase (MPO), most abundantly present in the granules of neutrophils, confirmed increased numbers of MPO+ neutrophils in the lung of Ifnar1−/− mice after influenza infection (Figure 1F).


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)

Ifnar1−/− mice are more susceptible to influenza infection than wild-type (WT) mice.(A) Survival and weight loss of WT and Ifnar1−/− mice after intranasal (i.n.) infection with 1×105 pfu or 2×104 pfu PR8 virus. (B) Viral load was measured by plaque assay in the lung of mice infected with 1×105 pfu PR8 virus at 2 (n = 6) and 5 (n = 11) days post infection (dpi). Total protein (C) and cytokine (D) levels were determined in the BALF of PR8-infected mice at 3 and 5 dpi. (C, D) Values are mean + SD and results are representative of three independent experiments with n>5 for each group. Histopathological scores (E) and representative photos (F) of lungs from WT and Ifnar1−/− mice (3 mice/group) after infection with 1×105 pfu PR8 virus and staining with H&E or MPO. Bars: 100 µm or 25 µm (enlarged pictures).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001304-g001: Ifnar1−/− mice are more susceptible to influenza infection than wild-type (WT) mice.(A) Survival and weight loss of WT and Ifnar1−/− mice after intranasal (i.n.) infection with 1×105 pfu or 2×104 pfu PR8 virus. (B) Viral load was measured by plaque assay in the lung of mice infected with 1×105 pfu PR8 virus at 2 (n = 6) and 5 (n = 11) days post infection (dpi). Total protein (C) and cytokine (D) levels were determined in the BALF of PR8-infected mice at 3 and 5 dpi. (C, D) Values are mean + SD and results are representative of three independent experiments with n>5 for each group. Histopathological scores (E) and representative photos (F) of lungs from WT and Ifnar1−/− mice (3 mice/group) after infection with 1×105 pfu PR8 virus and staining with H&E or MPO. Bars: 100 µm or 25 µm (enlarged pictures).
Mentions: Because many previous studies indicate a crucial role for IFN-I in host defense against influenza infection, we looked for crucial regulatory factors that are mainly regulated by IFN-I after influenza infection using Ifnar1−/− mice of B6 background. First we challenged Ifnar1−/− and WT mice with a lethal dose (1×105 pfu) of PR8 virus. The Ifnar1−/− mice started to die 5 days post infection (dpi) and all were dead within 8 dpi while approximately 50% of WT mice survived (Figure 1A). When we decreased the challenge dose of PR8 virus (2×104 pfu), virus infection killed Ifnar1−/− mice from 5 dpi and no mice survived at 13 dpi while 80% of WT B6 mice survived (Figure 1A). WT mice started to regain body weight 8 or 9 days after infection while Ifnar1−/− mice continued to lose weight until they died (Figure 1A). Since the contribution of IFN-I in viral clearance is controversial [22], [23], we next addressed viral titer in the lung at 2 and 5 dpi with influenza PR8 virus (1×105 pfu). Intriguingly, Ifnar1−/− mice showed higher viral titer in the lung than WT mice at 2 dpi but not at 5 dpi (Figure 1B). However, total protein levels were significantly higher in the bronchoalveolar lavage fluid (BALF) of Ifnar1−/− mice at 5 dpi than in WT mice (Figure 1C). Of note, significant levels of IL-6, TNF-α and IP-10 were determined at 3 dpi in the BALF of Ifnar1−/− mice and high levels IFN-γ and IL-6 at 5 dpi when compared with levels in WT mice (Figure 1D). Lung histopathology of WT and Ifnar1−/− mice after H&E staining revealed more edema, alveolar hemorrhage, alveolar wall thickness, and neutrophil infiltration in Ifnar1−/− mice than in WT mice at 5 dpi (Figure 1E and 1F). Staining specifically for myeloperoxidase (MPO), most abundantly present in the granules of neutrophils, confirmed increased numbers of MPO+ neutrophils in the lung of Ifnar1−/− mice after influenza infection (Figure 1F).

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