Negative regulation and immune effects of apoptotic cell clearance in the lung: SIRPa and miR34a.

Abstract

Apoptotic cell clearance (efferocytosis) is the essential biological process by which dead cells, called apoptotic cells (AC), are engulfed and recycled by living cells called phagocytes. This process is regulated by many receptors that differentiate between apoptotic and viable cells by recognizing molecules expressed on apoptotic cells, particularly a phospholipid called phosphatidylserine (PS). Binding of recognition receptors to PS leads to intracellular signaling, culminating in engulfment of the bound AC. Little is known about how this process is negatively regulated; most variation in engulfment capacity has been explained by the differing repertoires of AC recognition receptors on different phagocytes. In these chapters we describe two negative regulators of AC clearance: SIRPalpha and miR-34a. Both are highly expressed on the resident phagocyte of the alveolar space, the alveolar macrophage (AM). Both contribute to a low AM engulfment capacity. First, we show that expression of signal regulatory protein alpha (SIRPalpha), a previously described inhibitory receptor, is downregulated by treatment of AM with glucocorticoids, leading to increased efferocytosis. Second, we show that this glucocorticoid-augmented efferocytosis (GCAE) increases the susceptibility of mice to bacterial pneumonia. Third, we show miR-34a is a master-regulator of AC clearance in macrophages. We identify three target genes through which miR-34a can enhance AC uptake: Axl, Sirtuin1 (SIRT1) and GTP-ase regulator associated with focal adhesion kinase-1 (GRAF1). Finally, we show that expression of miR-34a alone increases macrophage bacterial killing. Collectively, these data suggest that limited AC uptake - rather than something to be "corrected" - is an important component of the AM identity and is integral to maintaining appropriate responses to potential lung pathogens.