NLRC4
NLR family CARD domain-containing protein 4 (CARD, LRR, and NACHT-containing protein) (Clan protein) (Caspase recruitment domain-containing protein 12) (Ice protease-activating factor) (Ipaf) [CARD12] [CLAN] [CLAN1] [IPAF] [UNQ6189/PRO20215]
Publications[править]
Inflamm-aging was recently affiliated with the progression of diabetic complications. Local cellular senescence together with senescence-associated secretory phenotype (SASP) are the main contributors to inflamm-aging. However, little is known about their involvement in diabetic periodontitis. Gingiva is the first line of host defense in the periodontium, and macrophages are key SASP-carrying cells. Here, we explored the molecular mechanism by which hyperglycemia drives the inflamm-aging in the gingival tissue of diabetic mice and macrophages. We demonstrated that hyperglycemia increased the infiltrated macrophage senescence in gingival tissue of diabetic mice. Simultaneously, hyperglycemia elevated the local burden of senescent cells in gingival tissue and induced the serum secretion of SASP factors [i]in vivo[/i] Moreover, [i]in vitro[/i], high glucose induced macrophage senescence and SASP factors secretion through phosphorylation of NLRC4, which further stimulated the NF-κB/Caspase-1 cascade via an IRF8-dependent pathway. Deletion of NLRC4 or IRF8 abolished hyperglycemia-induced cellular senescence and SASP in macrophages. In addition, we found that treatment with metformin inhibited NLRC4 phosphorylation and remarkably decreased cellular senescence and SASP in the context of hyperglycemia. Our data demonstrated that hyperglycemia induces the development of inflamm-aging in gingival tissue and suggested that NLRC4 is a potential target for treatment of diabetes-associated complications.
MeSH Terms
- Aging
- Animals
- Apoptosis Regulatory Proteins
- Blotting, Western
- Calcium-Binding Proteins
- Cellular Senescence
- Clustered Regularly Interspaced Short Palindromic Repeats
- Gingiva
- Glucose
- Hyperglycemia
- Immunohistochemistry
- Inflammation
- Interferon Regulatory Factors
- Male
- Mice
- Mice, Inbred C57BL
- RAW 264.7 Cells
- Signal Transduction
Keywords
- NLRC4
- SASP
- aging
- cellular senescence
- diabetes
- gingiva
- hyperglycemia
- inflamm-aging
- inflammasome
- inflammation
Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer's disease and Parkinson's disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins. Our findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1β. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac-YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age. Taken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain.
Keywords
- ASC
- Aging
- Caspase-1
- Inflammaging
- Inflammasome
- Inflammation
- Oxidative stress
Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N -acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.
MeSH Terms
- Adenine
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Blood Platelets
- Blood Pressure
- CARD Signaling Adaptor Proteins
- Caffeine
- Calcium-Binding Proteins
- Carotid Intima-Media Thickness
- Cell Line
- Cytidine
- Cytokines
- Female
- Humans
- Hypertension
- Immunoblotting
- Inflammasomes
- Inflammation
- Interleukin 1 Receptor Antagonist Protein
- Interleukin-1beta
- Intracellular Signaling Peptides and Proteins
- Macrophages
- Male
- Metabolomics
- Mice
- Middle Aged
- Monocytes
- Mortality
- Neutrophil Activation
- Neutrophils
- Nucleotides
- Oxidative Stress
- Phenotype
- Platelet Activation
- Pulse Wave Analysis
- Purinergic P1 Receptor Antagonists
- Regression Analysis
- Toll-Like Receptor 5
- Toll-Like Receptor 6
- Toll-Like Receptor 8
- Transcriptome
- Vascular Stiffness
- Young Adult
The mechanisms of kidney aging are not yet clear. Studies have shown that immunological inflammation is related to kidney aging. Inflammasomes are important components of innate immune system in the body. However, the function of inflammasomes and their underlying mechanisms in renal aging remain unclear. In this study, for the first time, we systematically investigated the role of the inflammasomes and the inflammatory responses activated by inflammasomes during kidney aging. We found that during kidney aging, the expression levels of the molecules associated with the activation of inflammasomes, including toll-like receptor-4 and interleukin-1 receptor (IL-1R), were significantly increased; their downstream signaling pathway molecule interleukin-1 receptor-associated kinase-4 (IRAK4) was markedly activated (Phospho-IRAK4 was obviously increased); the nuclear factor-κB (NF-κB) signaling pathway was activated (the activated NF-κB pathway molecules Phospho-IKKβ, Phospho-IκBα, and Phospho-NF-κBp65 were significantly elevated); the levels of the inflammasome components NOD-like receptor P3 (NLRP3), NLRC4, and pro-caspase-1 were prominently upregulated; and the proinflammatory cytokines IL-1β and IL-18 were notably increased in the kidneys of 24-month-old (elderly group) rats. These results showed that inflammasomes are markedly activated during the renal aging process and might induce inflamm-aging by promoting the maturation and secretion of the proinflammatory cytokines IL-1β and IL-18.
MeSH Terms
- Aging
- Animals
- Biomarkers
- Blotting, Western
- Fluorescent Antibody Technique
- Immunity, Innate
- Immunoenzyme Techniques
- Inflammasomes
- Kidney
- Kidney Function Tests
- Male
- Rats
- Rats, Inbred F344
- Real-Time Polymerase Chain Reaction
Keywords
- Inflamm-aging
- Inflammasome
- Inflammation
- Innate immune system
- Kidneys