Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

Weigt, S. Samuel; Palchevskiy, Vyacheslav; Belperio, John A.

doi:10.1172/jci93537

Cited by 78 publications

(66 citation statements)

References 78 publications

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“…Our results are consistent with studies showing an increased production of IL-1β after islet transplantation 15 and an activation of NLRP3 inflammasome during early insults, including ischemia/reperfusion injury, of transplanted solid organs 27 . We also found an increased expression of BBC3 after islet transplantation.…”

Section: Discussionsupporting

confidence: 92%

NLRP3 Inflammasome is Activated in Rat Pancreatic Islets by Transplantation and Hypoxia

Lavallard

Cottet‐Dumoulin

Wassmer

et al. 2020

Sci Rep

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Hypoxia, IL-1β production and oxidative stress are involved in islet graft dysfunction and destruction. However, the link between these events has not yet been determined in transplanted islets. The goal of this study was to determine whether NLRP3 inflammasome is responsible for IL-1β production and if it is activated by hypoxia-induced oxidative stress in transplanted islets. Rat islets were transplanted under the kidney capsule of immunodeficient mice. At different times post-transplantation, blood samples were collected and islet grafts harvested. Rat islets were also incubated in vitro either under normoxia or hypoxia for 24 h, in the absence or presence of inhibitors of NLRP3 inflammasome (CASP1 inhibitor) or oxidative stress (NAC). NLRP3, CASP1, IL1B, BBC3 pro-apoptotic and BCL2 antiapoptotic genes in transplanted and in vitro incubated islets were then studied using real time PCR. IL-1β released in the blood and in the supernatant was quantified by ELISA. Cell death was analysed by propidium iodide and Annexin-V staining. NLRP3, CASP1 and BBC3 in transplanted rat islets and IL-1β in blood transiently increased during the first days after transplantation. In islets incubated under hypoxia, NRLP3, IL1B and CASP1 and IL-1β released in supernatant increased compared to islets incubated under normoxia. These effects were prevented by the inhibition of NLRP3 inflammasome by CASP1 or oxidative stress by NAC. However, these inhibitors did not prevent hypoxia-induced rat islet death. These data show that NLRP3 inflammasome in rat islets is transiently activated after their transplantation and induced through oxidative stress in vitro. However, NRLP3 inflammasome inhibition does not protect islet cells against hypoxia.

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Section: Discussionsupporting

confidence: 92%

NLRP3 Inflammasome is Activated in Rat Pancreatic Islets by Transplantation and Hypoxia

Lavallard

Cottet‐Dumoulin

Wassmer

et al. 2020

Sci Rep

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“…A second signal, provided by diverse agonists, promotes indirect activation of the inflammasome, by ion, ROS, or ATP [29]. In light of the above, we focused our attention on the NLRP3 inflammasome because it was previously demonstrated that its excessive activity contributes to acute and chronic allograft rejection [30]. In this study, the activation of inflammasome complex was observed 28 days after transplantation by Western blot analysis, as demonstrated by high expression of NLRP3 and ASC in samples taken from the WT mice, while Fpr-1 gene deletion led to a reduced activation of all the members of the NLRP3 inflammatory complex, compared to other groups where there was a small and not significant reduction.…”

Section: Discussionmentioning

confidence: 99%

Modulation of NLRP3 Inflammasome through Formyl Peptide Receptor 1 (Fpr-1) Pathway as a New Therapeutic Target in Bronchiolitis Obliterans Syndrome

D’Amico

Fusco

Cordaro

et al. 2020

IJMS

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Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. We investigated, using transgenic mice, the mechanisms through which the deficiency of IL-1β/IL-18, Casp-1, or Fpr-1 genes could be protective in an experimental model of BOS, induced in mice by allogeneic heterotopic tracheal transplantation. Fpr-1 KO mice showed a marked reduction in histological markers of BOS and of mast cell numbers compared to other groups. Molecular analyses indicated that the absence of the Fpr-1 gene was able to decrease NF-κB nuclear translocation and modulate NLRP3 inflammasome signaling and the mitogen-activated protein kinase (MAPK) pathway in a more significant way compared to other groups. Additionally, Fpr-1 gene deletion caused a reduction in resistance to the apoptosis, assessed by the TUNEL assay. Immunohistochemical analyses indicated changes in nitrotyrosine, PARP, VEGF, and TGF-β expression associated with the pathology, which were reduced in the absence of the Fpr1 gene more so than by the deletion of IL-1β/IL-18 and Casp-1. We underline the importance of the NLRP3 inflammasome and the pathogenic role of Fpr-1 in experimental models of BOS, which is the result of the modulation of immune cell recruitment together with the modulation of local cellular activation, suggesting this gene as a new target in the control of the pathologic features of BOS.

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“…Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases and induce inflammation [18]. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome can be activated by many and diverse stimuli making NLRP3 the most importantly and clinically implicated inflammasome [19].…”

Section: Introductionmentioning

confidence: 99%

NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling

Ren

Tong

et al. 2017

Cell Physiol Biochem

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Background/Aims: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. Methods: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3^-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3^-/- mice. Results: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3^-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3^-/- mice. Conclusions: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.

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Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

Cited by 78 publications

References 78 publications

NLRP3 Inflammasome is Activated in Rat Pancreatic Islets by Transplantation and Hypoxia

NLRP3 Inflammasome is Activated in Rat Pancreatic Islets by Transplantation and Hypoxia

Modulation of NLRP3 Inflammasome through Formyl Peptide Receptor 1 (Fpr-1) Pathway as a New Therapeutic Target in Bronchiolitis Obliterans Syndrome

NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling

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