Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress

Mohammed, Sabira; Nicklas, Evan H.; Thadathil, Nidheesh; Selvarani, Ramasamy; Royce, Gordon H.; Kinter, Michael; Richardson, Arlan; Deepa, Sathyaseelan S.

doi:10.1016/j.freeradbiomed.2020.12.449

Cited by 82 publications

(109 citation statements)

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“…Because necroptosis and inflammation were reduced by dietary restriction and in Ames dwarf mice, we suggested that necroptosis plays a role in inflammaging [24,25]. Subsequently, we reported that necroptosis was increased in the liver of a mouse model of accelerated aging, mice deficient in the antioxidant enzyme, Sod1 [26]. Inhibition of necroptosis reduced expression of proinflammatory cytokines in the livers of Sod1 -/mice, supporting a role of necroptosis in ageassociated inflammation.…”

Section: Discussionmentioning

confidence: 88%

“…23.453580 doi: bioRxiv preprint Previously, we reported that necroptosis increases with age in the white adipose tissue of mice and interventions that delay aging (dietary restriction or Ames dwarf mice), reduced necroptosis and the expression of pro-inflammatory cytokines [24,25]. We also found that necroptosis was increased in a mouse model of accelerated aging (mice deficient in the antioxidant enzyme, Cu/Zn superoxide dismutase, Sod1 -/mice) and blocking necroptosis reduced inflammation in the liver of Sod1 -/mice [26]. Based on these data, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age.…”

Section: Introductionmentioning

confidence: 78%

“…Quantitative real-time PCR. Relative mRNA levels of necroptosis and inflammatory markers in mouse hippocampus, and cortical region of non-perfused brain was analyzed as described by Mohammed et al [26]. Briefly, total RNA was extracted using the RNeasy kit (Qiagen, Valencia, CA, USA) from 7-10 mg frozen cortex or hippocampus.…”

Section: Methodsmentioning

confidence: 99%

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Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Thadathil

Nicklas

Mohammed

et al. 2021

Preprint

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Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induce inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which causes membrane binding and permeabilization were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers (Iba-1 and GFAP) of neuroinflammation in the brains of old mice and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 78%

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Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Thadathil

Nicklas

Mohammed

et al. 2021

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“…One of the proposed mechanisms by which oxidative stress would enhance the inflammatory response is the induction and assembly of multiprotein complexes called inflammasomes. ROS activate the NOD-like receptor Pyrin domain 3 (NLRP3) in macrophages, triggering the formation of inflammasomes and an immune reaction that involves the synthesis of pro-inflammatory chemokines, from which CCL2 is, probably, the most representative [58][59][60][61]. This chemokine is upregulated following tissue injury and is expressed by both inflammatory and stromal cells.…”

Section: Mechanism Of Action Of Ccl2 In the Immune Response And Inflammation And Its Relationship With Multiple Metabolic Alterationsmentioning

confidence: 99%

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

Camps¹,

Castañé²,

Rodríguez-Tomàs³

et al. 2021

Preprint

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Infectious as well as most non-infectious diseases share certain common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors, produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, they produce metabolic alterations that influence the pathogenesis of the disease. In this review we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, which induces migration and infiltration of immune cells in target tissues, and is involved in disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.

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“…Previously, we reported that necroptosis increases with age in the white adipose tissue of mice and is reduced by interventions that delay aging (dietary restriction or in Ames dwarf mice) (Deepa et al, 2018;Royce et al, 2019). Recently, we found that necroptosis and inflammation are increased in the livers of a mouse model of accelerated aging (mice deficient in the antioxidant enzyme, Cu/Zn superoxide dismutase, Sod1 -/mice) and blocking necroptosis reduced inflammation in the livers of Sod1 -/mice (Mohammed et al, 2021). Based on these findings, we hypothesized that ageassociated increase in necroptosis might contribute to the age-related increase in hepatic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Necroptosis contributes to chronic inflammation and fibrosis in aging liver

Mohammed

Thadathil²,

Selvarani³

et al. 2021

Preprint

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Inflammaging, characterized by an increase in low-grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age-related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age-associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL-oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of proinflammatory cytokines (TNFα, IL6 and IL-1β), and markers of fibrosis were significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of proinflammatory cytokines relative to young mice. Short term treatment with the necroptosis inhibitor, necrostatin-1s (Nec-1s), reduced necroptosis, markers of M1 macrophages, expression of proinflammatory cytokines, and markers of fibrosis in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD.

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Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress

Cited by 82 publications

References 78 publications

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

Necroptosis contributes to chronic inflammation and fibrosis in aging liver

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