Phagocytosis and Resolution of Inflammation

21 September, 1998

Phagocytosis and Resolution of Inflammation

Apoptosis is defined in its strict sense a programmed cell death without inflammation, namely, without cell burst to release cellular components to cause inflammation. Apoptosis in vivo is therefore followed almost inevitably by rapid uptake of apoptotic cells into adjacent phagocytic cells. This is a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. More specifically here, what is the mechanism of the resolution of allergic inflammation? Why and how macrophages eat neutrophils at inflammatory sites and not the other way around?
ﾊAllergic inflammation is associated with infiltration of neutrophils, eosinophils, T cells, and macrophages. In allergen-induced cutaneous late-phase response, the numbers of infiltrating neutrophils and eosinophils peaked at 6 hr, persisted for 48 hr, but resolved completely by 7 days. In contrast, T-cell and macrophage numbers peaked between 24 and 72 hr after allergen challenge and persisted for up to 7 days (Ying S et al. 1997: uid=97164192). As the late-phase response was resolved, there was a progressive increase (peaking at 72 hr) in the total numbers of TUNEL-positive (apoptotic) neutrophils and eosinophils and in the numbers of macrophages that had engulfed these apoptotic cells and bodies. Very little apoptosis was associated with T cells or macrophages. These results suggest that phagocytosis by macrophages of apoptotic neutrophils and eosinophils may be a mechanism that regulates resolution of allergic inflammatory response. Fadok VA et al (1998: uid=98133964) also showed that phagocytosis of apoptotic neutrophils inhibited the production of IL-1beta, IL-8, IL-10, GM-CSF, and TNF-alpha, as well as leukotriene C4 and thromboxane B2 by human monocyte-derived macrophages. This phagocytsis seems to be a quiet process that does not lead to production of inflammatory mediators. What is then the fate of inflammatory macrophages? As shown in a murine model of resolving peritonitis (Bellingan GJ et al. 1996: uid=96399089), inflammatory macrophages emigrated rapidly (within 96 h) from the peritoneal cavity during the resolution of inflammation, whereas resident macrophages in the noninflamed peritoneum persisted for weeks. Emigrated macrophages were detected in the draining lymph nodes, but not in a variety of other tissues.

The mechanism by which macrophages ingest apoptotic neutrophils and eosinophils has also been of considerable interest. Several evidence (Stern M et al. 1996: uid=96374104) suggests that the ingestion is mediated by adhesive interactions between thrombospondin and macrophage alpha v beta 3 vitronectin receptor integrin and macrophage CD36. The epitope identified on amino acids 155-183 of human CD36 appears to be important and a synthetic peptide (155-169) inhibited phagocytosis (Navazo MD et al. 1996: uid=96279049). More recently, it was reported (Devitt A et al. 1998: uid=98208033) that the plasma-membrane glycoprotein CD14 linked with glycosylphosphatidylinositol on the surface of human macrophages was important for the recognition and clearance of apoptotic cells. CD14 could also act as a receptor that binds bacterial lipopolysaccharide (LPS), triggering inflammatory responses. The interaction of apoptotic cells with macrophages depended on a region of CD14 that was identical to, or at least closely associated with, a region known to bind LPS. It is of considerable interest to note that apoptotic cells, unlike LPS, do not provoke the release of pro- inflammatory cytokines from macrophages (rather suppress cytokine production as discussed above), whereas LPS triggers inflammatory responses that could lead to fatal toxic-shock syndrome. Again apoptosis here in vivo is a quit process of the resolution of inflammation.

In another recent paper (Wu YC and Horvitz HR, 1998: uid=98208032), a cell-migration protein was suggested to be essential for phagocytosis of apoptotic cells. This protein is required for the extension of cell surfaces to engulf apoptotic cells. Homologous proteins have been found in human (DOCK180), C. elegans (CED-5) and D. melanogaster (MBC) and are now designated the CDM (for CED-5, DOCK180 and MBC) family.

Why macrophages eat neutrophils and not the other way around remains to be investigated further. It is an important topic for the elucidation of cell-specific phagocytosis and for the resolution of inflammation that should give innovative ideas for drug development.　

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