Clearance of apoptotic cells: Implications in health and disease

Center for Cell Clearance and the Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2010; 189(7):1059-70. DOI: 10.1083/jcb.201004096
Source: PubMed


Recent advances in defining the molecular signaling pathways that regulate the phagocytosis of apoptotic cells have improved our understanding of this complex and evolutionarily conserved process. Studies in mice and humans suggest that the prompt removal of dying cells is crucial for immune tolerance and tissue homeostasis. Failed or defective clearance has emerged as an important contributing factor to a range of disease processes. This review addresses how specific molecular alterations of engulfment pathways are linked to pathogenic states. A better understanding of the apoptotic cell clearance process in healthy and diseased states could offer new therapeutic strategies.

Download full-text


Available from: Kodi Ravichandran
    • "Apoptotic cells are barely seen unengulfed by phagocytes in normal tissues, indicating that their removal occurs concurrently with progression of apoptosis (Franc, 2002;Gregory & Devitt, 2004;Henson & Hume, 2006;Lauber, Blumenthal, Waibel, & Wesselborg, 2004). Defects in the clearance of apoptotic cells may lead to inflammation, autoimmune responses, and developmental abnormalities (Elliott & Ravichandran, 2010;Hanayama & Nagata, 2005;Hanayama et al., 2004;Juncadella et al., 2013;Lu et al., 2011;Mahoney & Rosen, 2005;Mevorach, 2010;Munoz, Peter, Herrmann, Wesselborg, & Lauber, 2010;Nagata, Hanayama, & Kawane, 2010;Nathan & Ding, 2010;Poon, Lucas, Rossi, & Ravichandran, 2014). Clearance of apoptotic cells is performed by two types of phagocytes, " professional phagocytes, " such as macrophages and immature dendritic cells, whose main function is phagocytosis, and " nonprofessional " neighboring cells that in addition to their defined functions in tissues are also able to perform phagocytosis redundant and highly evolutionarily conserved genetic pathways were identified . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Programmed cell death and its specific form apoptosis play an important role during development of multicellular organisms. They are crucial for morphogenesis and organ sculpting as well as for adjusting cell number in different systems. Removal of apoptotic cells is the last critical step of apoptosis. Apoptotic cells are properly and efficiently recognized and eliminated through phagocytosis, which is performed by professional and nonprofessional phagocytes. Phagocytosis of apoptotic cells or apoptotic cell clearance is a dynamic multistep process, involving interactions between phagocytic receptors and ligands on apoptotic cells, which are highly conserved in evolution. However, this process is extremely redundant in mammals, containing multiple factors playing similar roles in the process. Using model organisms such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, and mouse permits addressing fundamental questions in developmental cell clearance by a comprehensive approach including powerful genetics and cell biological tools enriched by live imaging. Recent studies in model organisms have enhanced significantly our understanding of the molecular and cellular basis of apoptotic cell clearance during development. Here, we review the current knowledge and illuminate the great potential of the research performed in genetic models, which opens new directions in developmental biology.
    No preview · Article · Dec 2015 · Current Topics in Developmental Biology
  • Source
    • "If not successfully taken up by phagocytes, apoptotic cells proceed to the phase of late apoptosis when the plasma membrane becomes permeable for macromolecules [25]. The leakage of intracellular molecules during secondary necrosis provokes an inflammatory response [8], but the pre-treatment with LO-3 probably delay secondary necrosis triggered by the treatment with the nephrotoxic drugs and consequently inhibit the pro-inflammatory response. Associated with cell death/apoptosis, autophagy is a constitutive cellular event and is enhanced under certain conditions such drug treatments [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During therapeutic interventions, blood concentrations of intravenously applied drugs are higher, and their onset of pharmacological action is faster than with other routes of drug administration. However, acute drug therapy often produces nephrotoxic side effects, as commonly seen after treatment with Ketorolac or Gentamicin leading to questions about their use, especially for patients at risk for acute renal failure. Omega-6(n-6) and omega-3(n-3) polyunsaturated fatty acids (PUFA) affect eicosanoid metabolism, which plays a role in the regulation of inflammation. Eicosanoids derived from n-6 FA have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFA have anti-inflammatory and cytoprotective properties. We hypothesized that providing such injectable drugs with nephrotoxic potential in combination with n3-PUFAs from the outset, might afford rapid cytoprotection of renal cells, given the recent evidence that intravenously administered n3-PUFAs are rapidly incorporated into cell membranes. We used intraglomerular mesangial cells (MES13) that are sensitive to treatment with Ketorolac or Gentamicin instead of proximal tubular cells which do not respond to Ketorolac. We found a significant inhibition of Ketorolac (0.25, 0.5, 1 mM) or Gentamicin (2.5, 5 mM) induced cytotoxicity after pretreatment of MES13 cells with 0.01% of 20%w/v LipOmega-3 Emulsion 9/1, containing 90:10 wt/wt mixture of fish oil derived triglycerides to medium chain triglycerides.
    Full-text · Article · Oct 2014 · Toxicology Reports
  • Source
    • "Mobilized monocyte-derived macrophages extravasate to inflammatory tissue sites and clear apoptotic PMN in a nonphlogistic fashion by the process of efferocytosis . Apoptotic PMN release " find-me " signals that are sensed by extravasated macrophages [3]. Following phagocytosis, apoptotic PMN provides resolution cues to macrophages by evoking distinct signaling events that block release of proinflammatory mediators thus allowing further engulfment of apoptotic cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited. Methods: To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages. Results: VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses. Conclusion: VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.
    Full-text · Article · Sep 2014 · Mediators of Inflammation
Show more