Apoptosis and autoimmunity: When apoptotic cells break their silence

Franz, Sandra; Gaipl, Udo S.; Muñoz, Luis; Sheriff, Ahmed; Beer, Alexandra; Kalden, Joachim R.; Herrmann, Martin

doi:10.1007/s11926-006-0001-y

Cited by 31 publications

(19 citation statements)

References 24 publications

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“…Proper recognition, clearance, and degradation of apoptotic cell material are vital to maintaining an environment that protects the host against unchecked inflammation and eventual autoimmunity. Unengulfed apoptotic cells have the propensity to leak their cellular contents over time (secondary necrosis), resulting in inflammation, exposure of self-antigens, and a break in tolerance (Franz et al 2006). On the other hand, recognition of apoptotic cells can trigger the secretion of anti-inflammatory cytokines (such as TGF-b and IL-10) from the phagocyte, thereby dampening or resolving inflammation (Henson 2005;Elliott and Ravichandran 2010).…”

Section: Apoptotic Cell Digestion and Phagocyte Responsementioning

confidence: 99%

Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion

Hochreiter-Hufford

Ravichandran

2013

Cold Spring Harbor Perspectives in Biology

440

398

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Section: Apoptotic Cell Digestion and Phagocyte Responsementioning

confidence: 99%

Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion

Hochreiter-Hufford

Ravichandran

2013

Cold Spring Harbor Perspectives in Biology

440

398

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“…Engulfment) can be broken down into a series of steps, comprising recognition, internalization, phagosome maturation and finally lysosomal degradation of the apoptotic cell by the phagocyte. In mammals, impaired clearance of apoptotic cell corpses can lead to exposure of autoantigens, resulting in onset of autoimmune diseases, such as systemic lupus erythematosus 4,9,10 . Modulation of the engulfment process is therefore a potential therapeutic target in these conditions.…”

mentioning

confidence: 99%

“…and chronic polyarthritis 4,9,10 . Modulation of the engulfment process is therefore a potential therapeutic target in these conditions.…”

mentioning

confidence: 99%

A pathway for phagosome maturation during engulfment of apoptotic cells

et al. 2008

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The efficient removal of apoptotic cells is critical for the physiological well-being of the organism 1 Ã 4 ; defects in corpse removal have been linked to autoimmune disease 4,5 . While several players regulating the early steps of corpse recognition and internalization have been characterized 6 , the molecules and mechanisms relevant to the subsequent processing of the internalized corpses are poorly understood. Here, we identify a novel pathway for the processing of internalized apoptotic cells in C. elegans and in mammals. First, we show that RAB-5 and RAB-7 are sequentially recruited to phagosomes containing apoptotic corpses as they mature within phagocytes, and that both proteins are required for efficient corpse clearance. We then used targeted genetic screens to identify players regulating the recruitment and/or retention of Rab5 and Rab7 to phagosomes. Seven members of the HOPS complex (a Rab7 activator/effector complex) were required for Rab7 localization or retention on phagosomes. In an effort to identify factors that regulate Rab5 recruitment, we undertook an unbiased reverse genetic screen and identified 61 genes potentially required for corpse removal. In-depth analysis of two candidate genes, vps-34 and dyn-1/ dynamin, showed accumulation of internalized, but undegraded corpses within abnormal phagosomes that are defective in RAB-5 recruitment. Using a series of genetic and biochemical experiments in worms and mammalian cells, we ordered these proteins in a pathway, with DYN-1 functioning upstream of VPS-34, in the recruitment/retention of Rab5 to the nascent phagosome. Further, we identified a novel biochemical complex containing Vps34, dynamin and Rab5 GDP , providing a mechanism for Rab5 recruitment to the nascent phagosome.Removal of apoptotic cells (engulfment) is an essential process that occurs throughout life in multi-cellular animals as part of development, homeostasis, and wound healing1Ã4 , 7 , 8. Engulfment) can be broken down into a series of steps, comprising recognition, internalization, phagosome maturation and finally lysosomal degradation of the apoptotic cell by the phagocyte. In mammals, impaired clearance of apoptotic cell corpses can lead to exposure of autoantigens, resulting in onset of autoimmune diseases, such as systemic lupus erythematosus 4,9,10 . Modulation of the engulfment process is therefore a potential therapeutic target in these conditions. One of the fundamental challenges in understanding how defects in engulfment of apoptotic cells translates into diseased states is the identification of critical players involved in corpse removal and how these proteins orchestrate the different stages of engulfment.The nematode C. elegans represents a powerful genetic tool for the study of programmed cell death 11,12 . Large numbers of cells are induced to die during two periods in the life of a worm: during embryonic and larval morphogenesis and during germ cell development 13 . Genetic studies have identified two evolutionarily conserved signaling pathways invol...

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“…17 Along with the tightly controlled apoptotic program, highly efficient phagocytic mechanisms ensure prompt removal of apoptotic debris, thereby reducing the potential for apoptotic cells to become necrotic (secondary necrosis), resulting in inflammation. 18 In contrast to the immunologically silent apoptotic process, necrosis may stimulate inflammatory responses that could be harmful to tissue health. Despite the large number of cells dying by apoptosis in adult tissues, it is difficult to detect apoptotic cells even in tissues with high cell turnover such as the thymus.…”

Section: Apoptosis In Development and Maintenance Of Tissue Homeostasismentioning

confidence: 99%

Apoptotic membrane dynamics in health and disease

Julian¹,

Olson²

2015

CHC

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Apoptosis, also known as programmed cell death, is a fundamental homeostatic mechanism essential for normal embryonic development and the maintenance of healthy adult tissues. The processes that affect cell membrane dynamics during the tightly regulated apoptotic program have attracted considerable interest over the years. Distinct biochemical and structural alterations to plasma membrane composition and topography contribute to the efficient removal of cellular corpses. In this review, we will discuss these membrane alterations and their importance in maintaining cell and tissue homeostasis.

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Apoptosis and autoimmunity: When apoptotic cells break their silence

Cited by 31 publications

References 24 publications

Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion

Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion

A pathway for phagosome maturation during engulfment of apoptotic cells

Apoptotic membrane dynamics in health and disease

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