Proteinase-Activated Receptor-1, CCL2, and CCL7 Regulate Acute Neutrophilic Lung Inflammation

Abstract

PAR1 plays a central role in mediating the interplay between coagulation and inflammation, but its role in regulating acute neutrophilic inflammation is unknown. We report that antagonism of PAR1 was highly effective at reducing acute neutrophil accumulation in a mouse model of LPS-induced lung inflammation. PAR1 antagonism also reduced alveolar-capillary barrier disruption in these mice. This protection was associated with a reduction in the expression of the chemokines, CCL2 and CCL7, but not the proinflammatory cytokines, TNF and IL-6, or the classic neutrophil chemoattractants, CXCL1 and CXCL2. Antibody neutralization of CCL2 and CCL7 significantly reduced LPS-induced total leukocyte and neutrophil accumulation, recovered from the bronchoalveolar lavage fluid of challenged mice. Immunohistochemical analysis revealed that CCL2 predominantly localized to alveolar macrophages and pulmonary epithelial cells, whereas CCL7 was restricted to the pulmonary epithelium. In keeping with these observations, the intranasal administration of recombinant CCL2 (rCCL2) and rCCL7 led to the accumulation of neutrophils within the lung airspaces of naive mice in the absence of any underlying inflammation. Flow cytometry analysis further demonstrated an increase in Ly6G(hi) neutrophils expressing the chemokine receptors, CCR1 and CCR2, isolated from mouse lungs compared with circulating neutrophils. Conversely, the expression of CXCR2 decreased on neutrophils isolated from the lung compared with circulating neutrophils. Furthermore, this switch in chemokine receptor expression was accentuated after acute LPS-induced lung inflammation. Collectively, these findings reveal a novel role for PAR1 and the chemokines, CCL2 and CCL7, during the early events of acute neutrophilic inflammation.

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection

“…It has previously been shown that CCL7 also binds to CCR3 on eosinophils to induce chemotaxis and activation (19). Airway epithelial cells and macrophages produce CCL7, which may orchestrate cell recruitment in the context of oxidative stress (20,21). Induction of CCL7 during viral infections has been observed in asthmatic patients (22) and in models of RV infection dissecting the role of CCL2 (23).…”

A Functional Variant of Elafin With Improved Anti-inflammatory Activity for Pulmonary Inflammation

“…34,38 Additionally, MCP-1 has been shown to act as a neutrophil chemoattractant in a number of acute and chronic inflammatory models, with recent data suggesting that MCP-1 may have a significant and key role to play in neutrophil recruitment and infiltration in the lung. [38][39][40][41] It has also been proposed to indirectly regulate KC and MIP-2 expression during pulmonary Escherichia coli infection. 38 Furthermore, MCP-1 has been shown to play an important role in the bacterial clearance, and a deficiency of MCP-1 resulted in attenuation of immune cell influx as neutrophil and macrophages were reduced in MCP-1 −/− mice.…”

The mercurial nature of neutrophils: still an enigma in ARDS?

“…More recently, we have demonstrated that neutralizing CCL2, or the related chemokine CCL7, significantly diminishes neutrophil accumulation in the air spaces of LPS-challenged mice (123). Furthermore, neutrophils isolated from inflamed lungs displayed decreased expression of cell surface CXCR2 and increased expression of CCR1 and CCR2 (but not CCR3).…”

“…It is therefore becoming increasingly clear that the neutrophilic chemokine network within the lung is more complex than previously thought and may be dependent on the contextual influence of several inflammatory and chemotactic factors. It is also likely that the migration of neutrophils into various tissue microcompartments, for example endothelial vs. epithelial, is regulated by distinct sets of chemotactic cues differentially expressed within certain lung microenvironments (123), suggesting there may exist a significant amount of nonredundancy within the lung chemokine network (Tables 1 and 2). The functional capacity of individual chemokines may need to be considered within the context of the surrounding inflammatory milieu and the tissue compartment in which they operate.…”