Type I Interferon Signaling Regulates Ly6Chi Monocytes and Neutrophils during Acute Viral Pneumonia in Mice

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 Ly6Chi monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6Chi monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6Cint 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 Ly6Chi 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 Ly6Chi monocytes. Of note, WT BM reconstituted Ifnar1 −/− chimeric mice with increased numbers of Ly6Chi monocytes survived longer than influenza-infected Ifnar1 −/− mice. In contrast, WT mice that received Ifnar1 −/− BM cells with alternative Ly6Cint 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.

Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates

“…Indeed, type I IFNs mobilize inflammatory monocytes during viral infection in mice. 41,42 In addition, there is recent evidence that mDCs stimulated in vitro with LPS secrete high amounts of IL-10 43 ; however, we did not detect any transcriptional evidence of increased IL-10 production in the blood of animals treated with MPL.…”

Pivotal role of plasmacytoid dendritic cells in inflammation and NK-cell responses after TLR9 triggering in mice

“…46 Thus, our data clearly demonstrate the crucial role that pDCs play in monocyte/macrophage recruitment to the site of inflammation, probably via the modulation of chemokine production. Indeed, recent studies report that type I IFNs regulate monocyte/ macrophage and PMN recruitment during infection with MCMV, 47 influenza, 48 and Listeria monocytogenes 49 through the regulation of chemokine production.After the inoculation of BCG and E coli into the peritoneal cavity of IK L/L Rag Ϫ/Ϫ mice, we observed a significant decrease in monocyte/macrophage numbers. It should be mentioned that CCL5, which was not produced by pDC-deficient mice on TLR9 triggering, is required to prevent apoptosis of macrophages during infection with influenza virus.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Type I IFNs are produced in large quantities following viral infection and are regarded as the archetypal antiviral cytokine. The essential host-protective role for type I IFNs in controlling viral infection is exemplified by the observation that type I IFNR-deficient (Ifnar1 2/2 ) mice quickly succumb to a variety of viral infections compared with wild-type (WT) mice (4)(5)(6)(7)(8).…”