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.

Semaphorin 7A Aggravates Pulmonary Inflammation during Lung Injury.

The extent of pulmonary inflammation during lung injury ultimately determines patient outcome. Pulmonary inflammation is initiated by the migration of neutrophils into the alveolar space. Recent work has demonstrated that the guidance protein semaphorin 7A (SEMA7A) influences the migration of neutrophils into hypoxic tissue sites, yet, its role during lung injury is not well understood. Here, we report that the expression of SEMA7A is induced in vitro through pro-inflammatory cytokines. SEMA7A itself induces the production of pro-inflammatory cytokines in endothelial and epithelial cells, enhancing pulmonary inflammation. The induction of SEMA7A facilitates the transendothelial migration of neutrophils. In vivo, animals with deletion of SEMA7A expression showed reduced signs of pulmonary inflammatory changes following lipopolysaccharide challenge. We define here the role of SEMA7A in the development of lung injury and identify a potential pathway to interfere with these detrimental changes. Future anti-inflammatory strategies for the treatment of lung injury might be based on this finding.