Semaphorin 7A coordinates Neutrophil response during pulmonary inflammation and sepsis.

RATIONALE: Pulmonary defense mechanisms are critical for host integrity during pneumonia and sepsis. This defense is fundamentally dependent on the activation of neutrophils during the innate immune response. Recent work has shown that Semaphorin 7A (Sema7A) holds significant impact on platelet function, yet its role on neutrophil function within the lung is not well understood. OBJECTIVE: To identify the role of Sema7A during pulmonary inflammation and sepsis. MEASUREMENTS AND MAIN RESULTS: In ARDS patients we were able to show a correlation between Sema7A and oxygenation levels. During subsequent workup we found that Sema7A binds to the neutrophil PlexinC1 receptor, increasing integrins and L-selectin on neutrophils. Sema7A prompted neutrophil chemotaxis in-vitro and the formation of platelet-neutrophil complexes in-vivo. We also observed altered adhesion and transmigration of neutrophils in Sema7A-/- animals in the lung during pulmonary inflammation. This effect resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pulmonary sepsis. This finding was associated with significantly worse outcome of Sema7A-/- animals in a model of pulmonary sepsis. CONCLUSIONS: Sema7A has an immunomodulatory effect in the lung affecting pulmonary sepsis and ARDS. This effect influences the response of neutrophils to external aggression and might influence patient outcome.

Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A2B-receptor on blood cells.

Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils into the different compartments of the lung. Recent studies showed evidence that the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 influence migration of immune cells and their activity was linked to adenosine concentrations. We investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important anti-inflammatory role in the lung. After LPS-inhalation for 45 minutes, administration of the CXCR4-inhibitor (AMD3100) decreased transendothelial and transepithelial migration, whereas CXCR7-antagonism influenced epithelial migration exclusively. In A2B-/- mice, no anti-inflammatory effects were detectible through either one of the agents. Using chimeric mice, we identified A2B on hematopoietic cells to be crucial for these anti-inflammatory effects of CXCR4/7-inhibition. Both inhibitors decreased TNFα, IL6, CXCL1 and CXCL2/3 levels in the bronchoalveolar lavage of wild type mice, while not influencing the chemokine release in A2B-/- mice. Inflammation augmented the expression of both receptors and their inhibition increased A2B-levels upon inflammation. In vitro assays with human epithelium/endothelium confirmed our in vivo findings. During inflammation, inhibition of CXCR4- and CXCR7-receptors prevented microvascular permeability in wild type but not in A2B-/- mice, highlighting the pivotal role of an active A2B-receptor in this setting. The combination of both inhibitors had a synergistic effect in preventing capillary leakage. In conclusion, we determined the pivotal role of CXCR4- and CXCR7-inhibition in acute pulmonary inflammation, which depended on A2B-receptor signalling.