Control of Neutrophil activation through Semaphorin 7A-Plexin C1 is essential for immune defense during pulmonary sepsis

ABSTRACT Pulmonary defense mechanisms are critical for host integrity during the early phase of pneumonia and sepsis. These processes are fundamentally dependent on the activation of neutrophils during the early phase of the innate immune response. Recent work has shown that semaphorin 7A (Sema7A) holds significant impact on platelet activation, yet its role in neutrophil migration and function is not well known. We report here that Sema7A binds to neutrophil PlexinC1, increasing integrins and L-selectin on the neutrophil surface. Sema7A-induced neutrophil activation also 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. Sema7A-/- animals also showed altered crawling properties of neutrophils. This resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pneumonia-induced pulmonary sepsis. This was associated with significantly worse outcome of Sema7A-/- animals in a model of Klebsiella pneumoniae . Furthermore, we were able to show a correlation between serum levels of Sema7A in patients with ARDS and oxygenation levels. Thus, we show here that Sema7A has an immunomodulatory effect though which might influence patient outcome during pulmonary sepsis. Summary Sema7A controls pulmonary immune defense