Mechanisms of Toll-Like Receptor 4 (TLR4)-Mediated Inflammation After Cold Ischemia/Reperfusion in the Heart

Kaczorowski, David J.; Nakao, Atsunori; Vallabhaneni, Raghuveer; Mollen, Kevin P.; Sugimoto, Ryujiro; Kohmoto, Junichi; Zuckerbraun, Brian S.; McCurry, Kenneth R.; Billiar, Timothy R.

doi:10.1097/tp.0b013e3181a36e5e

Cited by 99 publications

(86 citation statements)

References 59 publications

(53 reference statements)

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“…TLRs play critical roles in many disease conditions, including the pathogenesis of atherosclerosis (25, 26), chronic cardiac allograft rejection (27), liver and heart ischemia/reperfusion injury (28)(29)(30), and type 1 diabetes (31)(32)(33). Several groups have demonstrated that TLR4 activation is directly involved in the chronic rejection of transplanted organs (27,34).…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Rocuts

Zhang

et al. 2010

The Journal of Immunology

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Islet allografts from donor mice exposed to CO are protected from immune rejection after transplantation via the suppression of membrane trafficking/activation of TLR4 in islets/β cells. The molecular mechanisms of how CO suppresses TLR4 activation in β cells remain unclear and are the focus of this study. Cells of the insulinoma cell line, βTC3, were stably transfected with pcDNA3-TLR4-YFP and pDsRed-Monomer-Golgi plasmids and used to identify the subcellular distribution of TLR4 before and after LPS stimulation by confocal microscopy. Immunofluorescence analysis revealed that TLR4 mainly resides in the Golgi apparatus in βTC3 cells when in a quiescent state. LPS stimulation led to a rapid trafficking of TLR4 from the Golgi to the cell membrane. Physical interaction between TLR4 and myeloid differentiation factor-2 (MD-2) was confirmed by immunoprecipitation. Depleting MD-2 using small interfering RNA or blocking the N-glycosylation of cells using tunicamycin blocked membrane trafficking of TLR4. Pre-exposing cells to CO at a concentration of 250 parts per million suppressed membrane trafficking of TLR4 via inhibiting its glycosylation and the interaction between TLR4 and MD-2. In conclusion, MD-2 is required for the glycosylation of TLR4 and its consequent membrane trafficking in βTC3 cells. CO suppresses membrane activation of TLR4 via blocking its glycosylation and the physical interaction between TLR4 and MD-2.

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Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Rocuts

Zhang

et al. 2010

The Journal of Immunology

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“…TLR4-deficient mice are also protected during hepatic ischemia-reperfusion injury. Compelling evidence using TLR4-defective mice also supports a role for a HMGB1-TLR4 axis in hemorrhagic shock/resuscitation-induced injury, systemic inflammation, and end-organ damage induced by bilateral femur fractures (81,82).…”

Section: Hmgb1 Trauma and Sterile Inflammationmentioning

confidence: 99%

HMGB1 and RAGE in Inflammation and Cancer

Sims¹,

Rowe²,

Rietdijk

et al. 2010

Annu. Rev. Immunol.

1,222

1,096

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The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.

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“…Our results indicate that factor B synthesis and release is highly dependent on MyD88, but independent of TLR9. We have previously demonstrated that myocardial injury after cold I/R is also largely dependent on MyD88 (50). RNA polymerase III has also been shown to detect DNA in the cytosol and trigger activation of the immune system through RIG-I (51,52).…”

Section: Discussionmentioning

confidence: 99%

Mammalian DNA Is an Endogenous Danger Signal That Stimulates Local Synthesis and Release of Complement Factor B

Kaczorowski

Scott

Pibris

et al. 2012

Mol Med

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Complement factor B plays a critical role in ischemic tissue injury and autoimmunity. Factor B is dynamically synthesized and released by cells outside of the liver, but the molecules that trigger local factor B synthesis and release during endogenous tissue injury have not been identified. We determined that factor B is upregulated early after cold ischemia-reperfusion in mice, using a heterotopic heart transplant model. These data suggested upregulation of factor B by damage-associated molecular patterns (DAMPs), but multiple common DAMPs did not induce factor B in RAW264.7 mouse macrophages. However, exogenous DNA induced factor B mRNA and protein expression in RAW cells in vitro, as well as in peritoneal and alveolar macrophages in vivo. To determine the cellular mechanisms involved in DNA-induced factor B upregulation we then investigated the role of multiple known DNA receptors or binding partners. We stimulated peritoneal macrophages from wild-type (WT), toll-like receptor 9 (TLR9)-deficient, receptor for advanced glycation end products (RAGE) -/-and myeloid differentiation factor 88 (MyD88) -/-mice, or mouse macrophages deficient in high-mobility group box proteins (HMGBs), DNA-dependent activator of interferon-regulatory factors (DAI) or absent in melanoma 2 (AIM2), with DNA in the presence or absence of lipofection reagent. Reverse transcription-polymerase chain reaction, Western blotting and immunocytochemical analysis were employed for analysis. Synthesis of factor B was independent of TLR9, RAGE, DAI and AIM2, but was dependent on HMGBs, MyD88, p38 and NF-κB. Our data therefore show that mammalian DNA is an endogenous molecule that stimulates factor B synthesis and release from macrophages via HMGBs, MyD88, p38 and NF-κB signaling. This activation of the immune system likely contributes to damage following sterile injury such as hemorrhagic shock and ischemia-reperfusion.

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Mechanisms of Toll-Like Receptor 4 (TLR4)-Mediated Inflammation After Cold Ischemia/Reperfusion in the Heart

Cited by 99 publications

References 59 publications

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

Carbon Monoxide Suppresses Membrane Expression of TLR4 via Myeloid Differentiation Factor-2 in βTC3 Cells

HMGB1 and RAGE in Inflammation and Cancer

Mammalian DNA Is an Endogenous Danger Signal That Stimulates Local Synthesis and Release of Complement Factor B

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