Semaphorin 7A coordinates Neutrophil response during pulmonary inflammation and sepsis

• Semaphorin 7A controls integrins on neutrophils, neutrophil chemotaxis and influences the formation of platelet-neutrophil complexes.

• Sema7A influences the early phase of inflammation, which is relevant to the outcome in murine experimental 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.