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

Grabiec, Aleksander M.; Hussell, Tracy

The receptors that mediate efferocytosis often have antiinflammatory signalling consequences that can change the phenotype and function of the ingesting cell. For example, engagement and activation of TAM receptors inhibits signalling pathways triggered by cytokines and toll-like receptor ligands through induction of suppressor of cytokine signalling-1 and 3 (SOCS-1 and 3) [49, 50] (see Fig. 1a , b). The impact of apoptotic cell clearance on cell function depends on the cell type mediating efferocytosis, which in turn depends on tissue location. In the lung, efferocytosis is mediated predominantly by macrophages and airway epithelial cells, with most consequences studied in the former. In macrophages, efferocytosis increases the secretion of the antiinflammatory cytokines, transforming growth factor-β (TGF-β) and interleukin (IL)-10 [51, 52] , while inhibiting secretion of proinflammatory mediators such as TNF-α, IL-1, IL-8 and leukotriene C4 [53, 54] . IL-10 production by macrophages upon apoptotic cell contact is, in part, dependent upon the scavenger receptor CD36 [51] and TSP-1, which links macrophages to apoptotic cells in cooperation with integrin αvβ3 [55] . Efferocytosis also upregulates prostaglandin E2 (PGE2) and impairs FcRmediated phagocytosis [54, 56] , and intratracheal instillation of apoptotic cells enhances the resolution of LPSinduced acute pulmonary inflammation [57] . This change in function from pro-inflammatory to pro-resolution can be observed as a phenotypic switch from an M1-to an M2-like macrophage phenotype and includes the induction of peroxisome proliferator-activated receptor-γ (PPARγ) [58] . However, this is likely to be context-, cell-type-and tissue-dependent. For example, nitric oxide, but not IL-10, TGF-β or PGE2, mediates the immunosuppressive effects induced by apoptotic cell efferocytosis in dendritic cells [59] . It is also interesting to note that efferocytosis by dendritic cells appears to be subset-specific. Only CD103 + murine lung dendritic cells capture and present apoptotic cell-associated antigen in health and disease, whereas both the CD11b hi and the CD103 + dendritic cells ingest and traffic latex beads or soluble antigen [60] . Whether this is due to selective expression of receptors recognising apoptotic cells or a phenotypic switch after ingestion is not currently known. Therefore, clearance of apoptotic cells has profound influences on the ingesting cell. Though the outcome has predominantly been studied for macrophages, other cell types, particularly dendritic cells, are also likely to be affected. [19] and humans [20] Stabilin-2 Not studied