Regulation of Neutrophilic Inflammation by Proteinase-Activated Receptor 1 during Bacterial Pulmonary Infection
Open Access
- 15 June 2015
- journal article
- Published by The American Association of Immunologists
- Vol. 194 (12), 6024-6034
- https://doi.org/10.4049/jimmunol.1500124
Abstract
Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin–antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1β, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1β, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators.Keywords
This publication has 60 references indexed in Scilit:
- High-resolution crystal structure of human protease-activated receptor 1Nature, 2012
- Interleukin-1 beta Regulates CXCL8 Release and Influences Disease Outcome in Response to Streptococcus pneumoniae, Defining Intercellular Cooperation between Pulmonary Epithelial Cells and MacrophagesInfection and Immunity, 2012
- Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signalingProceedings of the National Academy of Sciences of the United States of America, 2011
- Importance of CXC Chemokine Receptor 2 in Alveolar Neutrophil and Exudate Macrophage Recruitment in Response to Pneumococcal Lung InfectionInfection and Immunity, 2010
- Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injuryJCI Insight, 2009
- Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary FibrosisAmerican Journal of Respiratory and Critical Care Medicine, 2009
- Pyogenic Bacterial Infections in Humans with MyD88 DeficiencyScience, 2008
- Differential Contribution of Bacterial N -Formyl-Methionyl-Leucyl- Phenylalanine and Host-Derived CXC Chemokines to Neutrophil Infiltration into Pulmonary Alveoli during Murine Pneumococcal PneumoniaInfection and Immunity, 2007
- 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damageNature Immunology, 2007
- Understanding the Inflammatory Cytokine Response in Pneumonia and SepsisArchives of Internal Medicine, 2007