The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation

Grabiec, Aleksander M.; Hussell, Tracy

Finally, the observations that aberrant expression and activity of the TAM receptor Axl has an oncogenic function in haematological and epithelial malignancies triggered the interest in targeting the activity of PtdSer recognition receptors, and a small molecule inhibitor of Axl is currently in phase I clinical trials [139] . However, preclinical studies indicate that pharmacological modulators of PtdSer recognition receptors might have a significant impact on the immune system, especially in the context of lung immunopathology. In light of the critical role of Axl in resolution of lung inflammation upon influenza infection [2] , any attempts to target Axl activity systemically should proceed with caution due to potential adverse events related to exaggerated inflammatory responses to respiratory infections. Similar to Axl, MerTK signalling is also required for silencing of lung inflammation: inhibition of MerTK proteolytic cleavage by the ADAM17 inhibitor TAPI-0 restores MerTK expression and attenuates inflammation during LPS-induced lung injury [140] , whereas administration of a MerTK blocking antibody has the opposite effect [141] . These results suggest that activating antibodies or compounds which prevent shedding of TAM receptors could be beneficial in the context chronic lung diseases. Indeed, TAM receptors can be activated independently of apoptotic cell engulfment by specific antibodies [46, 142] , though their effects have not been tested in models of lung inflammation. In that regard, it is noteworthy that activation of TAM receptors leads to shedding of their extracellular domains and soluble forms of TAM receptors can act as decoy receptors and suppress apoptotic cell engulfment by macrophages [143] . Although alterations in the levels of soluble TAM receptors are noted in several pathologies [144, 145] , their physiological role is still poorly understood. It remains unknown if administration of antibodies targeting TAM receptors would cause their sequestration and what consequences it would have for the immune homeostasis of the lung.