Autoimmunity and the Clearance of Dead Cells

Nagata, Shinji; Hanayama, Rikinari; Kawane, Kohki

doi:10.1016/j.cell.2010.02.014

Cited by 759 publications

(724 citation statements)

References 129 publications

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“…Receptors such as BAI1 can signal intracellularly through the ELMO1-DOCK180-Rac signaling module to stimulate cytoskeletal rearrangement and engulfment. 12 Stabilin-2 has been reported to require the adapter protein GULP and thymosinβ 4 to engulf apoptotic cells. 19,20 Once internalized, phagolysosome maturation occurs through the action of several Rab-family GTPases eventually leading to the degradation of the ingested cell corpse.…”

Section: Steps Involved In Clearancementioning

confidence: 99%

“…Although there are known receptors for S1P (S1PR [1][2][3][4][5] ), the specific GPCR involved in phagocyte migration is unclear. Phagocytes can express several S1P receptors making it difficult to determine the receptor(s) involved.…”

Section: Steps Involved In Clearancementioning

confidence: 99%

“…4 For these reasons both the dying cell and the phagocyte communicate and engage each other to ensure successful engulfment.…”

mentioning

confidence: 99%

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Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

2016

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The turnover and clearance of cells is an essential process that is part of many physiological and pathological processes. Improper or deficient clearance of apoptotic cells can lead to excessive inflammation and autoimmune disease. The steps involved in cell clearance include: migration of the phagocyte toward the proximity of the dying cells, specific recognition and internalization of the dying cell, and degradation of the corpse. The ability of phagocytes to recognize and react to dying cells to perform efficient and immunologically silent engulfment has been well-characterized in vitro and in vivo. However, how apoptotic cells themselves initiate the corpse removal and also influence the cells within the neighboring environment during clearance was less understood. Recent exciting observations suggest that apoptotic cells can attract phagocytes through the regulated release of 'find-me' signals. More recent studies also suggest that these find-me signals can have additional roles outside of phagocyte attraction to help orchestrate engulfment. This review will discuss our current understanding of the different find-me signals released by apoptotic cells, how they may be relevant in vivo, and their additional roles in facilitating engulfment.

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Section: Steps Involved In Clearancementioning

confidence: 99%

Section: Steps Involved In Clearancementioning

confidence: 99%

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Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

2016

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“…Those apoptotic cells (AC) need to be rapidly and efficiently removed otherwise they will produce necrotic debris that promotes hyper-activation of the immune system, leading to autoimmune diseases like SLE. 1,2 Professional phagocytes, macrophages and dendritic cells (DC), efficiently engulf AC thereby preventing the release of pro-inflammatory molecules. 3 Moreover, recognition and engulfment of AC by macrophages and DC serves to sustain immune tolerance to self-antigens by virtue of the anti-inflammatory cytokines IL-10 and TGF-β released from these cells, and the recruitment of natural regulatory T cells.…”

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confidence: 99%

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Tian

Lee

et al. 2016

Cell Death Differ

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Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f genedeficient mice are predisposed to develop a lupus-like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with FcγRIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens.

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“…Each mammalian cell carries about 6 pg of DNA, which is actively degraded by a group of enzymes (DNases) in physiological situations (6,7). DNase II located in lysosomes (8) digests the DNA of apoptotic cells and of nuclei expelled from erythroid precursors (9,10).…”

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confidence: 99%

Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

Kawane

Tanaka

Kitahara

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wildtype mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II −/− macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFα, IL-1β, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFα, IL-1β, or IL-6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFα, IL-1β, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase IInull mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis.inflammation | macrophages | apoptosis | DNase II | engulfment

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Autoimmunity and the Clearance of Dead Cells

Cited by 759 publications

References 129 publications

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

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