TREM-1 Attenuates RIPK3-mediated Necroptosis in Hyperoxia-induced Lung Injury in Neonatal Mice

Syed, Mansoor Ali; Shah, Dilip; Das, Pragnya; Andersson, Sture; Pryhuber, Gloria S.; Bhandari, Vineet

doi:10.1165/rcmb.2018-0219oc

Cited by 27 publications

(18 citation statements)

References 46 publications

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“…TREM-1 seems to be a hypoxia-inducible gene in myeloid DCs and TECs (52, 143) and might be involved in regulated cell death through amplification of inflammatory signals leading to necroptosis and pyroptosis, as has been shown in brain microglia (144). Interestingly, however, TREM-1 was also shown to mediate an inhibitory effect on necroptosis and pyroptosis in neonatal lung tissue, as suggested in previous work by Syed et al (145). In our hands, in the early phase of renal IRI, TREM-1 modulation did not affect tubular damage or renal function (146).…”

Section: Trem-1mentioning

confidence: 67%

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

et al. 2020

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Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra-and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and Tammaro et al. Innate Immunity in Renal IRI mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research.

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Section: Trem-1mentioning

confidence: 67%

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

et al. 2020

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“…Enhancing FAO by L-carnitine protects against hyperoxia-induced increase in (dihydro)ceramide and apoptosis. In addition to apoptosis, hyperoxia exposure causes necroptosis in neonatal lungs (42). We did not determine whether decreased FAO seen in O 2 /rec results in necroptosis in lung ECs.…”

Section: Discussionmentioning

confidence: 94%

Fatty Acid Oxidation Protects against Hyperoxia-induced Endothelial Cell Apoptosis and Lung Injury in Neonatal Mice

Yao¹,

Gong

Peterson³

et al. 2019

Am J Respir Cell Mol Biol

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In neonates, hyperoxia or positive pressure ventilation causes continued lung injury characterized by simplified vascularization and alveolarization, which are the hallmarks of bronchopulmonary dysplasia. Although endothelial cells (ECs) have metabolic flexibility to maintain cell function under stress, it is unknown whether hyperoxia causes metabolic dysregulation in ECs, leading to lung injury. We hypothesized that hyperoxia alters EC metabolism, which causes EC dysfunction and lung injury. To test this hypothesis, we exposed lung ECs to hyperoxia (95% O 2 /5% CO 2) followed by air recovery (O 2 /rec). We found that O 2 /rec reduced mitochondrial oxidative phosphorylation without affecting mitochondrial DNA copy number or mitochondrial mass and that it specifically decreased fatty acid oxidation (FAO) in ECs. This was associated with increased ceramide synthesis and apoptosis. Genetic deletion of carnitine palmitoyltransferase 1a (Cpt1a), a rate-limiting enzyme for carnitine shuttle, further augmented O 2 /rec-induced apoptosis. O 2 /rec-induced ceramide synthesis and apoptosis were attenuated when the FAO was enhanced by L-carnitine. Newborn mice were exposed to hyperoxia (.95% O 2) between Postnatal Days 1 and 4 and were administered L-carnitine (150 and 300 mg/kg, i.p.) or etomoxir, a specific Cpt1 inhibitor (30 mg/kg, i.p.), daily between Postnatal Days 10 and 14. Etomoxir aggravated O 2 /rec-induced apoptosis and simplified alveolarization and vascularization in mouse lungs. Similarly, arrested alveolarization and reduced vessel numbers were further augmented in EC-specific Cpt1a-knockout mice compared with wild-type littermates in response to O 2 /rec. Treatment with L-carnitine (300 mg/kg) attenuated O 2 /rec-induced lung injury, including simplified alveolarization and decreased vessel numbers. Altogether, enhancing FAO protects against hyperoxia-induced EC apoptosis and lung injury in neonates.

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“…Receptor-interacting protein kinase 3 (RIPK3) may play a role in this association (47). Hyperoxic exposure is also associated with increased RIPK3 expression in the lung (48,49). The findings of impaired fatty acid oxidation in ventilator-induced lung injury may be generalizable to other forms of acute lung injury, especially in the setting of a high supply of exogenous fatty acids that overwhelms mitochondrial uptake ability.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity

Plataki¹,

Fan²,

Sánchez³

et al. 2019

JCI Insight

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TREM-1 Attenuates RIPK3-mediated Necroptosis in Hyperoxia-induced Lung Injury in Neonatal Mice

Cited by 27 publications

References 46 publications

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

Fatty Acid Oxidation Protects against Hyperoxia-induced Endothelial Cell Apoptosis and Lung Injury in Neonatal Mice

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity

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