Activation of the small G-protein Rac by human rhinovirus attenuates the TLR3/IFN-α axis while promoting CCL2 release in human monocyte-lineage cells.
Although rhinoviral infections, a major cause of asthma exacerbations, occur predominantly in upper airway bronchial epithelial cells, monocytic-lineage cells are implicated in establishing the inflammatory microenvironment observed during the disease. Human rhinovirus (HRV) is unique in that nearly genetically identical viruses bind either the ICAM-1 or low-density lipoprotein receptor (LDL-R). Within minutes of binding, HRV is capable of eliciting a signaling response in both epithelial cells and monocyte-derived macrophages. It is unclear whether this signaling response is important to the subsequent release of inflammatory mediators, particularly in cells not capable of supporting viral replication. We show here that the small molecular mass G-protein Rac is activated following exposure of macrophages to HRV serotypes known to be ICAM-1- and LDL-R-tropic. We demonstrate that inhibiting Rac resulted in the upregulation of TLR3 in macrophages exposed to major- and minor-group HRV, and resulted in increased release of IFN-α. Furthermore, inhibiting Rac in HRV-exposed macrophages attenuated activation of the stress kinase p38 and release of the pro-inflammatory cytokine CCL2, but inhibiting Rac did not affect release of the pro-inflammatory cytokine CCL5. These findings suggest that Rac is an important regulator in establishing the inflammatory microenvironment that is initiated in the human airway upon exposure to rhinovirus.
Department of Chemistry, Lawrence University, Appleton, WI, USA.
Michael T
MT
Schreiber
Bryce
B
Schuler
LuYuan
L
Li
David J
DJ
Hall
D019070:Cell Lineage; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D020559:Monomeric GTP-Binding Proteins / Q000276:immunology; D010850:Picornaviridae Infections / Q000276:immunology*; D012229:Rhinovirus / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*
D018932:Chemokine CCL2; D018836:Inflammation Mediators; D016898:Interferon-alpha; D051196:Toll-Like Receptor 3; D020559:Monomeric GTP-Binding Proteins; D020744:rac GTP-Binding Proteins