Increased immunogenicity is an integral part of the heat shock response following renal ischemia

Bidmon, Bettina; Kratochwill, Klaus; Rusai, Krisztina; Kuster, Lilian; Eickelberg, Oliver; Aufricht, Christoph

doi:10.1007/s12192-011-0314-2

Cited by 10 publications

(7 citation statements)

References 73 publications

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“…Nevertheless, we show that loss of biglycan leads to reduction of HSP70 expression, which is associated with a decreased pro-inflammatory signaling and a less severe inflammation. Several studies have shown that pharmacological HSP70 induction protects renal tissue from IRI damage [81][82][83]. Our data suggest that in ROS-mediated renal inflammation targeting biglycan and consequently inhibiting HSP70 expression might limit renal pathology.…”

Section: Ros-dependent Nlrp3 Inflammasome Activationmentioning

confidence: 56%

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

et al. 2016

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Biglycan, a ubiquitous proteoglycan, acts as a danger signal when released from the extracellular matrix. As such, biglycan triggers the synthesis and maturation of interleukin-1β (IL-1β) in a Toll-like receptor (TLR) 2-, TLR4-, and reactive oxygen species (ROS)-dependent manner. Here, we discovered that biglycan autonomously regulates the balance in IL-1β production in vitro and in vivo by modulating expression, activity and stability of NADPH oxidase (NOX) 1, 2 and 4 enzymes via different TLR pathways. In primary murine macrophages, biglycan triggered NOX1/4-mediated ROS generation, thereby enhancing IL-1β expression. Surprisingly, biglycan inhibited IL-1β due to enhancement of NOX2 synthesis and activation, by selectively interacting with TLR4. Synthesis of NOX2 was mediated by adaptor molecule Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF). Via myeloid differentiation primary response protein (MyD88) as well as Rac1 activation and Erk phosphorylation, biglycan triggered translocation of the cytosolic NOX2 subunit p47(phox) to the plasma membrane, an obligatory step for NOX2 activation. In contrast, by engaging TLR2, soluble biglycan stimulated the expression of heat shock protein (HSP) 70, which bound to NOX2, and consequently impaired the inhibitory function of NOX2 on IL-1β expression. Notably, a genetic background lacking biglycan reduced HSP70 expression, rescued the enhanced renal IL-1β production and improved kidney function of Nox2(-/y) mice in a model of renal ischemia reperfusion injury. Here, we provide a novel mechanism where the danger molecule biglycan influences NOX2 synthesis and activation via different TLR pathways, thereby regulating inflammation severity. Thus, selective inhibition of biglycan-TLR2 or biglycan-TLR4 signaling could be a novel therapeutic approach in ROS-mediated inflammatory diseases.

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Section: Ros-dependent Nlrp3 Inflammasome Activationmentioning

confidence: 56%

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

et al. 2016

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“…Class Ia DAMPs such as HMGB1 and HSPs are generated in reperfusion‐injured organs including human renal allografts , but also emitted under BD conditions . These molecules considerably contribute to creation of sterile inflammation including IRI‐mediated inflammation when sensed by those members of the NLR or ALR family that form inflammasomes .…”

Section: A Plethora Of Damps and An Attempt To Classify Themmentioning

confidence: 99%

Transplantation and Damage-Associated Molecular Patterns (DAMPs)

Land

Agostinis

Gasser

et al. 2016

American Journal of Transplantation

133

110

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Upon solid organ transplantation and during cancer immunotherapy, cellular stress responses result in the release of damage-associated molecular patterns (DAMPs). The various cellular stresses have been characterized in detail over the last decades, but a unifying classification based on clinically important aspects is lacking. Here, we provide an in-depth review of the most recent literature along with a unifying concept of the danger/injury model, suggest a classification of DAMPs, and review the recently elaborated mechanisms that result in the emission of such factors. We further point out the differences in DAMP responses including the release following a heat shock pattern, endoplasmic reticulum stress, DNA damage-mediated DAMP release, and discuss the diverse pathways of regulated necrosis in this respect. The understanding of various forms of DAMPs and the consequences of their different release patterns are prerequisite to associate serum markers of cellular stresses with clinical outcomes.

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“…Small children receiving adult size kidneys are at increased risk of DGF and thrombosis, possibly as a result of their low cardiac output in relation to the transplanted organ [4,5]. Ischaemia‐reperfusion injury is involved in the development of DGF and cellular lesions play a role in up‐regulating the expression of class II MHC [6,7].…”

Section: Introductionmentioning

confidence: 99%

Improved GFR and renal plasma perfusion following remote ischaemic conditioning in a porcine kidney transplantation model

Soendergaard¹,

Krogstrup²,

Secher³

et al. 2012

Transplant International

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Summary Delayed graft function (DGF) complicates approximately 25% of kidney allografts donated after brain death (DBD). Remote ischaemic conditioning (rIC) involves brief, repetitive, ischaemia in a distant tissue in connection with ischaemia/reperfusion in the target organ. rIC has been shown to induce systemic protection against ischaemic injuries. Using a porcine kidney transplantation model with donor (63 kg) recipient (15 kg) size mismatch, we investigated the effects of recipient rIC on early renal plasma perfusion and GFR. Brain death was induced in donor pigs (n = 8) and kidneys were removed and kept in cold storage until transplantation. Nephrectomized recipient pigs were randomized to rIC (n = 8) or non‐rIC (n = 8) with one kidney from the same donor in each group. rIC consisted of 4 × 5 min clamping of the abdominal aorta. GFR was significantly higher in the rIC group compared with non‐rIC (7.2 ml/min vs. 3.4 ml/min; ΔGFR = 3.7 ml/min, 95%‐CI: 0.3–7.2 ml/min, P = 0.038). Renal plasma perfusion in both cortex and medulla measured by dynamic contrast‐enhanced magnetic resonance imaging (MRI) was significantly higher over time in the rIC group compared with non‐rIC. This experimental study demonstrated a positive effect of rIC on early graft perfusion and function in a large animal transplantation model.

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Increased immunogenicity is an integral part of the heat shock response following renal ischemia

Cited by 10 publications

References 73 publications

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

Transplantation and Damage-Associated Molecular Patterns (DAMPs)

Improved GFR and renal plasma perfusion following remote ischaemic conditioning in a porcine kidney transplantation model

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