Role of the PlexinB1 / Semaphorin4D axis for the control of inflammation during lung injury

• Applicant: Professor Dr. Peter Rosenberger
• Subject Area: Anaesthesiology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324452025

The presence of dysregulated inflammation, inappropriate accumulation of leukocytes an altered permeability of the alveolar barrier remain the central pathophysiologic changes of lung injury and the adult respiratory distress syndrome. In this process the migration of granulocytes and the orchestration of the inflammatory response are still incompletely understood. The search for novel therapies for conditions associated with inflammation has indicated that neuronal guidance proteins (NGP) might have significant influence on conditions caused by acute inflammation. NGPs and their target receptors were originally described in the context of axonal development but recent years have shown that they also might influence mechanisms of acute inflammation. In previous work we were able to show that the guidance protein Semaphorin7A and its receptor play an important role during hypoxic and pulmonary inflammation. We have now extended this work and describe a role for Semaphorin4D (Sema4D) and PlexinB1 (PLXNB1) during inflammation causing lung injury. In preliminary experiments we were able to demonstrate that Sema4D and PlexinB1 are significantly regulated during inflammation in vitro. These changes in expression translate into altered formation of platelet neutrophil complexes and also changed severity of pulmonary inflammation in a model of LPS induced lung injury. These results propose an important role for the Sema4D-PlexinB1 axis during the development of pulmonary inflammation and lung injury. Therefore we plan here to further investigate the interaction of Sema4D and PlexinB1 with known mechanisms of leukocyte recruitment. Furthermore we aim to describe the functional implications of the Sema4D-PlexinB1 axis for the development and maintenance of lung injury and in a last step we aim to elucidate potential novel therapeutic options derived from these findings.

• DFG Programme: Research Grants