Autophagy Contributes to Caspase-independent Macrophage Cell Death

Xu, Yue; Kim, Sung Ouk; Li, Yilei; Han, Jiahuai

doi:10.1074/jbc.m513377200

Cited by 211 publications

(181 citation statements)

References 57 publications

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“…Because suppression of autophagy results in cell death, this observation is consistent with the above in vitro results. Although TLR4 stimulation alone cannot induce cell death, it can if the pan-caspase inhibitor z-VAD-fmk is present (34,35). Under this in vitro experimental setting, a marked enhancement of macrophage cell death was observed in the absence of HMGB1 (Fig.…”

Section: Resultsmentioning

confidence: 88%

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

Yanai

Matsuda

et al. 2013

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

164

156

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High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1-floxed (Hmgb1 f/f ) mice to achieve the conditional inactivation of the gene in a cell-and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions. LPS | IL-1β | IL-18

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Section: Resultsmentioning

confidence: 88%

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

Yanai

Matsuda

et al. 2013

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

164

156

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“…14 When caspase activity and NF-kB are blocked, full-length RIP1 is responsible for inducing TLR4-induced necrosis 56 (Figure 7a). More recently, Xu et al 57 demonstrated autophagy in macrophages following treatment with LPS/zVAD-fmk. TRIF, RIP1 and ROS production, as well as poly-(ADP-ribose) polymerase-1 (PARP) activation, seem to be involved in inducing autophagy, which contributes to caspase-independent macrophage cell death.…”

Section: Role Of Rip1 In Death Receptor Signallingmentioning

confidence: 99%

RIP1, a kinase on the crossroads of a cell's decision to live or die

et al. 2007

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Binding of inflammatory cytokines to their receptors, stimulation of pathogen recognition receptors by pathogen-associated molecular patterns, and DNA damage induce specific signalling events. A cell that is exposed to these signals can respond by activation of NF-jB, mitogen-activated protein kinases and interferon regulatory factors, resulting in the upregulation of antiapoptotic proteins and of several cytokines. The consequent survival may or may not be accompanied by an inflammatory response. Alternatively, a cell can also activate death-signalling pathways, resulting in apoptosis or alternative cell death such as necrosis or autophagic cell death. Interplay between survival and death-promoting complexes continues as they compete with each other until one eventually dominates and determines the cell's fate. RIP1 is a crucial adaptor kinase on the crossroad of these stress-induced signalling pathways and a cell's decision to live or die. Following different upstream signals, particular RIP1-containing complexes are formed; these initiate only a limited number of cellular responses. In this review, we describe how RIP1 acts as a key integrator of signalling pathways initiated by stimulation of death receptors, bacterial or viral infection, genotoxic stress and T-cell homeostasis. Cell Death and Differentiation (2007) 14, 400-410. doi:10.1038/sj.cdd.4402085Receptor interacting protein (RIP) kinases constitute a family of seven members, all of which contain a kinase domain (KD) (Figure 1a). They are crucial regulators of cell survival and death 1 (Figure 2). Based on sequence similarities, mode of regulation and substrate specificities of their catalytic domain, RIP kinases are classified as serine/threonine kinases and are closely related to members of the interleukin-1-receptorassociated kinase (IRAK) family. RIP1 and RIP2 (CARDIAK/ RICK) also bear a C-terminal domain belonging to the death domain (DD) superfamily, namely, a DD and a caspase recruitment domain (CARD), respectively, allowing recruitment to large protein complexes initiating different signalling pathways. The unique C-terminus of RIP3 bears a RIP homotypic interaction motif (RHIM), which is also present in the intermediate domain (ID) of RIP1. This RHIM domain is sufficient for interaction of RIP1 with RIP3. 1 RIP4 (DIK/PKK) and RIP5 (SgK288) are characterized by the presence of ankyrin repeats in their C-terminal domains. 1 RIP6 (LRRK1) and RIP7 (LRRK2) are RIP members containing a leucine-rich repeat (LRR) motif 1 that may be involved in recognition of pathogen-, damage-or stress-associated molecular patterns (PAMP, DAMP, SAMP). In addition, they harbor Roc/COR domains (Ras of complex proteins/C-terminal of Roc). Binding of GTP to the GTPase-like Roc domain leads to the stimulation of LRRK1 kinase activity. 2 Mutation analysis indicated that the COR domain might be important for transmitting the stimulating signal to the KD. 2 The function of RIP6 and RIP7 is yet unknown; however, mutations in the human LRRK2 gene are associated with both fam...

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“…Inhibition of autophagy using siRNA against Beclin-1 and Atg5 reduced etoposide-induced cell death, suggesting that these cells died an autophagic cell death. Another study found that lipopolysaccharide treatment induced caspase-independent cell death in macrophages that were inhibited by siRNA-mediated knockdown of Beclin-1 or pre-treatment with 3-MA or Wortmannin [69]. In addition, treatment with hydrogen peroxide or 2-methoxyestradiol (2-ME) to inhibit Superoxide Dismutase are both known to induce apoptosis in cells [70,71], was recently shown to induce autophagic cell death in HEK293 and U87 cells [72].…”

Section: Autophagy and Programmed Cell Deathmentioning

confidence: 99%

Recycle or die: The role of autophagy in cardioprotection

Gustafsson

Gottlieb

2008

Journal of Molecular and Cellular Cardiology

173

153

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Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggragates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy is essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.

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Autophagy Contributes to Caspase-independent Macrophage Cell Death

Cited by 211 publications

References 57 publications

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection

RIP1, a kinase on the crossroads of a cell's decision to live or die

Recycle or die: The role of autophagy in cardioprotection

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