NLRP3 Inflammasome Modulates Post-Burn Lipolysis and Hepatic Fat Infiltration via Fatty Acid Synthase

Vinaik, Roohi; Stanojcic, Mile; Jeschke, Marc G.

doi:10.1038/s41598-018-33486-9

Cited by 23 publications

(18 citation statements)

References 24 publications

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“…Readouts such as elevated plasma IL-6 at 24 h post-insult, chronic inflammasome activation, loss of body mass, wound healing impaired by excessive angiogenesis, loss of glycaemic control, elevated markers of oxidative stress, immune dysregulation and neurodegenerative consequences, among others, have emerged as emblematic of the progression of PICS. [22][23][24][25][26][27] In a previous study, 15 the possible effect of iron in the efficacy of nephrilin peptide in a rat scald model was suggested. Here we show that, in both sexes of rats, the addition of equimolar ferric iron (but not ferrous iron or zinc) roughly doubles the efficacy of the peptide in the model.…”

Section: Discussionmentioning

confidence: 99%

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma

Mascarenhas

Ayadi

Ravikumar

et al. 2020

Scars, Burns & Healing

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Introduction: Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to suppress neuroinflammation, loss of body mass, glycaemic control and kidney function in a rat scald model, as well as sepsis mortality in a mouse model. The present study explores the effect of nephrilin plus iron formulations on clinically relevant outcomes in the rat scald model. Methods: Animals were treated with nephrilin by subcutaneous bolus injection on post-burn days 1–7. Equimolar ferric iron in the formulation improved the positive systemic effects of nephrilin on kidney function, glycaemic control, oxidative stress, early hyperinflammation, late inflammasome activation, hyperangiogenesis and body mass, all variables previously shown to bear upon clinically relevant burn injury outcomes. The sparing effects of nephrilin-iron were demonstrated in both sexes. Discussion: Surprisingly, optimum daily treatment doses were in the range of 2–4 mg/kg, while 8 mg/kg was less effective, suggesting the possibility of marginal pro-oxidant effects from the ‘free’ iron fraction. Thus, although ferric iron in the nephrilin formulation is clearly helpful, care must be exercised to select an optimum treatment dose. Conclusion: Iron increases the efficacy of nephrilin peptide in burns.

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Section: Discussionmentioning

confidence: 99%

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma

Mascarenhas

Ayadi

Ravikumar

et al. 2020

Scars, Burns & Healing

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“…The activation of caspase-1 occurs upon the activation of inflammasomes which induces the degradation of pro-caspase-1 (pro-form) to caspase-1 (active form) 4 . Therefore, the regulation of inflammasomes by pharmacological inhibitors is considered as an efficient strategy to reduce IL-1β levels in various inflammatory and immune diseases 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells

Lee

Yang

et al. 2019

Sci Rep

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Tumor microenvironment favors tumor cells to promote their growth and metastasis such as migration, invasion, and angiogenesis. IL-1β, one of the inflammatory cytokines released from myeloid cells in tumor microenvironment, plays an important role in development and progress of tumor. The activation of inflammasome is a critical step to secrete mature IL-1β through stepwise reactions to activate capspase-1. Therefore, we investigated whether the inhibition of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in macrophages regulated the metastatic potential of tumor cells. NLRP3 inflammasome was activated by ATP in bone marrow-derived primary mouse macrophages. The metastatic potential of mouse melanoma cell line (B16F10) was determined by migration and invasion assays with transwell system. ATP-treated wild-type macrophages increased the migration and invasion of melanoma cells. However, NLRP3- or caspase-1-knockout macrophages exhibited greatly diminished ability to promote the migration and invasion of melanoma cells. In addition, treatment with celastrol, an inhibitor of NLRP3 inflammasome, reduced the potency of macrophages to stimulate migration and invasion of melanoma cells. The results demonstrate that inhibition of the NLRP3 inflammasome in macrophages by genetic deficiency or a pharmacological inhibitor is linked to suppression of the metastatic potential of tumor cells. The results would provide a novel anti-cancer strategy to modulate tumor microenvironment by suppressing NLRP3 inflammasome and consequently reducing IL-1β production.

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“…DAMP molecules are known to significantly contribute to systemic inflammation and adverse outcomes in trauma [22, 23]. We have previously shown that NLRP3 activation is central to post-burn responses including the induction of ER stress and systemic inflammation [17, 24, 25]. Pro-inflammatory cytokines such as IL-6 and IL-1β can lead to ER stress highlighting a positive feedback loop promoting inflammatory signaling [26–28].…”

Section: Introductionmentioning

confidence: 99%

Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

Andersohn

Garcia

Fan

et al. 2019

Preprint

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24Chronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite 25 activation of the unfolded protein response. We have shown that traumatic injury such as a 26 severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last 27 for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory 28 responses is not clear. Here we show that induction of chronic ER stress leads to the release of 29 known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are 30 aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells 31 which are then capable of polarizing naïve T cells. Our findings indicate that induction of 32 chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in 33 persistent systemic inflammation and adverse outcomes. 34 35 Introduction 36The endoplasmic reticulum (ER) is the site of secretory and membrane-bound protein 37 synthesis. Under conditions where ER protein synthesis rates exceed the folding capacity of the 38 ER, unfolded or misfolded proteins accumulate in the ER lumen or membrane. The presence of 39 an excess of misfolded proteins in the ER results in the activation of ER stress signaling 40 pathways to restore homeostasis [1]. For example, ER chaperone content is increased while 41 global protein synthesis rates are decreased in an effort to resolve the folding stress. If ER 42 luminal protein folding stress cannot be resolved, pro-apoptotic pathways are activated resulting 43 in cell death [2, 3]. Chronic ER stress is characterized by activation of this pathway without 44 significant cell death resulting in cellular and organ dysfunction over extended time periods [4]. 45Inflammatory stimuli can lead to chronic ER stress in multiple cells and tissues [5]. For example, 46 activation of the acute phase response results in dramatic upregulation in the synthesis of 47 secretory proteins such as C-reactive protein resulting in hepatic ER stress [6, 7]. We previously 48 found that chronic ER stress is prominent post-burn injury and persists for an extended period 49 after the initial insult [8][9][10][11][12][13][14][15][16][17]. How chronic ER stress mechanistically contributes to post-burn 50 inflammation and metabolic dysfunction is still unclear. 51 NLR Family Pyrin Domain Containing 3 (NLRP3) plays a central role in regulating 52 inflammatory signaling transmitted by damage-associated molecular pattern molecules (DAMPs) 53 derived from stressed or damaged cells [18, 19]. Inflammatory DAMPs include intracellular 54 proteins such as high mobility group box 1 (HMBG1) and non-protein DAMPs such as nucleic 55 acids, both of which are released from dying/damaged cells. Inflammasome activation by 56DAMPs leads to caspase 1 activation, resulting in maturation and secretion of IL-1β and 57 downstream inflammatory responses [20, 21]. DAMP molecules are known to significantly 58 contribute to systemic inflammation and adverse o...

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NLRP3 Inflammasome Modulates Post-Burn Lipolysis and Hepatic Fat Infiltration via Fatty Acid Synthase

Cited by 23 publications

References 24 publications

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma

Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma

Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells

Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

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