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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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IFN-I signaling on hematopoietic cell lineage helps protect mice from lethal influenza infection.Bone marrow (BM) cells from naïve WT (W) or Ifnar1−/− (K) mice were grafted to lethally irradiated WT or Ifnar1−/− recipient mice. (A–C) Sets of BM grafted mice were challenged with influenza PR8 virus (1×105 pfu) and analyzed at 3 dpi. (A) Number of monocytes (Mo) and neutrophils (N) were determined. (B) Expression levels of MCP-1 and KC were measured in BALF. (C) Monocytes in the lung were pooled and cultured for 4 h to measure chemokine production in vitro. Values are mean + SD of triplicate experiments with n>4 for each group. (D) Mice were challenged with lethal dose of influenza PR8 (1×105 pfu) and survival was monitored for 2 weeks. W→W (n = 17), K→W (n = 16), W→K (n = 16), and K→K (n = 11). Data were pooled from three independent experiments.
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ppat-1001304-g006: IFN-I signaling on hematopoietic cell lineage helps protect mice from lethal influenza infection.Bone marrow (BM) cells from naïve WT (W) or Ifnar1−/− (K) mice were grafted to lethally irradiated WT or Ifnar1−/− recipient mice. (A–C) Sets of BM grafted mice were challenged with influenza PR8 virus (1×105 pfu) and analyzed at 3 dpi. (A) Number of monocytes (Mo) and neutrophils (N) were determined. (B) Expression levels of MCP-1 and KC were measured in BALF. (C) Monocytes in the lung were pooled and cultured for 4 h to measure chemokine production in vitro. Values are mean + SD of triplicate experiments with n>4 for each group. (D) Mice were challenged with lethal dose of influenza PR8 (1×105 pfu) and survival was monitored for 2 weeks. W→W (n = 17), K→W (n = 16), W→K (n = 16), and K→K (n = 11). Data were pooled from three independent experiments.

Mentions: To clarify the origin and roles of monocytes in depth in the absence of IFN-I signaling, we used BM chimeric mice. Ifnar1−/− recipient mice reconstituted with WT BM cells (W→K) have significantly more Ly6Chi monocytes than K→K (Ifnar1−/− donor and Ifnar1−/− recipient) mice (Figure 6A). Concomitantly, the MCP-1 level in the BALF was correlated with Ly6Chi monocytes (i.e., W→W and W→K) after influenza infection (Figure 6B). The fact that K→W mice elicited no higher level of MCP-1 than found in the BALF of K→K mice after influenza infection suggests that radio-resistant WT parenchymal cells do not play a major role in MCP-1 production (Figure 6B). In addition, Ly6Chi monocytes derived from W→W and W→K mice produce MCP-1 efficiently following in vitro culture (Figure 6C), clearly indicating that Ly6Chi monocytes derived from WT BM mice exclusively produce MCP-1 in response to influenza infection. To the contrary, although we saw a distinct correlation between KC production with IFN-I deficiency in monocytes (Figure 6C), W→K chimera mice still had significantly augmented KC in BALF even with high levels of MCP-1 and Ly6Chi monocytes (Figure 6B). Thus it seems likely that the complete regulation of KC also needs the IFN-I-dependent signaling pathway in cells other than monocytes or there may be another regulator for KC in the absence of IFN-I signaling.


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)

IFN-I signaling on hematopoietic cell lineage helps protect mice from lethal influenza infection.Bone marrow (BM) cells from naïve WT (W) or Ifnar1−/− (K) mice were grafted to lethally irradiated WT or Ifnar1−/− recipient mice. (A–C) Sets of BM grafted mice were challenged with influenza PR8 virus (1×105 pfu) and analyzed at 3 dpi. (A) Number of monocytes (Mo) and neutrophils (N) were determined. (B) Expression levels of MCP-1 and KC were measured in BALF. (C) Monocytes in the lung were pooled and cultured for 4 h to measure chemokine production in vitro. Values are mean + SD of triplicate experiments with n>4 for each group. (D) Mice were challenged with lethal dose of influenza PR8 (1×105 pfu) and survival was monitored for 2 weeks. W→W (n = 17), K→W (n = 16), W→K (n = 16), and K→K (n = 11). Data were pooled from three independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3044702&req=5

ppat-1001304-g006: IFN-I signaling on hematopoietic cell lineage helps protect mice from lethal influenza infection.Bone marrow (BM) cells from naïve WT (W) or Ifnar1−/− (K) mice were grafted to lethally irradiated WT or Ifnar1−/− recipient mice. (A–C) Sets of BM grafted mice were challenged with influenza PR8 virus (1×105 pfu) and analyzed at 3 dpi. (A) Number of monocytes (Mo) and neutrophils (N) were determined. (B) Expression levels of MCP-1 and KC were measured in BALF. (C) Monocytes in the lung were pooled and cultured for 4 h to measure chemokine production in vitro. Values are mean + SD of triplicate experiments with n>4 for each group. (D) Mice were challenged with lethal dose of influenza PR8 (1×105 pfu) and survival was monitored for 2 weeks. W→W (n = 17), K→W (n = 16), W→K (n = 16), and K→K (n = 11). Data were pooled from three independent experiments.
Mentions: To clarify the origin and roles of monocytes in depth in the absence of IFN-I signaling, we used BM chimeric mice. Ifnar1−/− recipient mice reconstituted with WT BM cells (W→K) have significantly more Ly6Chi monocytes than K→K (Ifnar1−/− donor and Ifnar1−/− recipient) mice (Figure 6A). Concomitantly, the MCP-1 level in the BALF was correlated with Ly6Chi monocytes (i.e., W→W and W→K) after influenza infection (Figure 6B). The fact that K→W mice elicited no higher level of MCP-1 than found in the BALF of K→K mice after influenza infection suggests that radio-resistant WT parenchymal cells do not play a major role in MCP-1 production (Figure 6B). In addition, Ly6Chi monocytes derived from W→W and W→K mice produce MCP-1 efficiently following in vitro culture (Figure 6C), clearly indicating that Ly6Chi monocytes derived from WT BM mice exclusively produce MCP-1 in response to influenza infection. To the contrary, although we saw a distinct correlation between KC production with IFN-I deficiency in monocytes (Figure 6C), W→K chimera mice still had significantly augmented KC in BALF even with high levels of MCP-1 and Ly6Chi monocytes (Figure 6B). Thus it seems likely that the complete regulation of KC also needs the IFN-I-dependent signaling pathway in cells other than monocytes or there may be another regulator for KC in the absence of IFN-I signaling.

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