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Activated platelets release micromolar concentrations of the chemokine CXCL4/Platelet Factor-4. Deposition of CXCL4 onto the vascular endothelium is involved in atherosclerosis, facilitating monocyte arrest and recruitment by an as yet, unidentified receptor. Here, we demonstrate that CXCL4 drives chemotaxis of the monocytic cell line THP-1. Migration and intracellular calcium responses induced by CXCL4 were pertussis toxin-sensitive, implicating a GPCR in signal transduction. Cell treatment with chondroitinase ABC ablated migration, suggesting that cis presentation of CXCL4 by cell surface glycosaminoglycans to a GPCR is required. Although CXCR3 has been previously described as a CXCL4 receptor, THP-1 cells were unresponsive to CXCR3 ligands and CXCL4-induced migration was insensitive to a CXCR3 antagonist, suggesting that an alternative receptor is involved. Interrogating CC-class chemokine receptor transfectants, we unexpectedly found that CXCL4 could induce the migration of CCR1-expressing cells and also induce CCR1 endocytosis. Extending our findings to primary human monocytes, we observed that CXCL4 induced CCR1 endocytosis and could induce monocyte chemotaxis in a CCR1 antagonist-sensitive manner. Collectively, our data identify CCR1 as a previously elusive monocyte CXCL4 receptor and suggest that CCR1 may play a role in inflammation where the release of CXCL4 is implicated.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections, especially in infants. Lung neutrophilia is a hallmark of RSV disease but the mechanism by which neutrophils are recruited and activated is unclear. Here, we investigate the innate immune signaling pathways underlying neutrophil recruitment and activation in RSV-infected mice. We show that MyD88/TRIF signaling is essential for lung neutrophil recruitment while MAVS signaling, leading to type I IFN production, is necessary for neutrophil activation. Consistent with that notion, administration of type I IFNs to the lungs of RSV-infected Mavs−/− mice partially activates lung neutrophils recruited via the MyD88/TRIF pathway. Conversely, lack of neutrophil recruitment to the lungs of RSV-infected Myd88/Trif−/− mice can be corrected by administration of chemoattractants and those neutrophils become fully activated. Interestingly, Myd88/Trif−/− mice did not have increased lung viral loads during RSV infection, suggesting that neutrophils are dispensable for viral control. Thus, two distinct pathogen sensing pathways collaborate for neutrophil recruitment and full activation during RSV infection.

Respiratory Syncytial Virus (RSV) is the single most important cause of acute lower respiratory tract infections in infants. Most children are infected with RSV by the age of two, and the majority of them suffer only a simple cold. However, 1- 3% develop severe bronchiolitis that requires hospitalisation and these children have a greater risk of developing recurrent wheeze and asthma-like symptoms in later childhood. There is currently no treatment or vaccine against RSV. Despite its prevalence, the characteristics of RSV infection and spread in the host lung are not well characterised. Stromal cells are the functionally connective tissue of the lung and include alveolar type I and II (ATI/ATII) epithelial cells, endothelial cells and fibroblasts. These cells are slowly being recognised as important players in the response to respiratory infections through their expression of proinflammatory mediators and tissue repair proteins. However, the role of stromal cells in RSV infection in vivo has not been elucidated. We have been able to identify several important chemokines, cytokines and growth factors that are expressed by stromal cells in response to RSV in vivo using fluorescent activated cell sorting and gene expression analysis. Interestingly, our data show that ATII epithelial cells are a major source of growth factors while the non-epithelial, non-endothelial stromal cells are a major source of chemokines. In addition, when infecting lung fibroblasts ex vivo with RSV, many chemokines known to be important during RSV infection are produced. We further demonstrate that expression of several of these mediators in vivo is dependent on IFNAR signalling, illustrating the cellular crosstalk between stromal cells and alveolar macrophages in the lung during RSV infection, which is needed for effective viral clearance. Finally, we highlight the potential protective role of ATII epithelial cell-derived GM-CSF expression in the lung during RSV infection in vivo. Data from these experiments reveal novel and previously unknown roles of stromal cells in the response to RSV infection in vivo and highlight new targets, which could be modulated for potential therapeutic benefits.