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

Abstract

Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections.

Keywords: Airway macrophage; Apoptotic cell clearance; Efferocytosis; Inflammation; Lung; Phosphatidylserine.

Fig. 1

The many roles of apoptotic cell recognition and phagocytosis in immunity and infection. a Efferocytosis leads to removal of apoptotic cells without release of their content. When apoptotic cells are not engulfed in a timely manner, they undergo secondary necrosis and release necrotic cell debris which subsequently causes uncontrolled inflammatory activation of the innate immune system by the released ‘damage associated molecular patterns’ (DAMPS). b During apoptosis, cells expose phosphatidylserine (PtdSer) on the outer leaflet of their membranes, which is recognised by specific receptors expressed on phagocytes. Recognition of PtdSer by TAM receptors through bridging molecules Gas6 and Protein S triggers a signalling cascade which converges on upregulation of suppressor of cytokine signalling-1 and 3 (SOCS3), which act as negative regulators of the immune response. Activation of TAM receptors by apoptotic cells inhibits production of proinflammatory cytokines, such as TNFα and IL-6, while promoting expression of factors that suppress inflammation and promote tissue repair, including IL-10 and TGF-β. c Some enveloped viruses express PtdSer on their envelopes and use PtdSer recognition receptors, such as TAM and TIM receptor families, to promote infection of the host cells and evade the immune response. d During microbial infections with intracellular pathogens, induction of apoptosis of infected cells is one of the strategies of the host immune system to facilitate pathogen clearance. For example, in case of Mycobacterium tuberculosis (Mtb) infections, necrosis of infected cells leads to dissemination of bacteria, whereas engulfment of infected cells undergoing apoptosis allows for pathogen destruction