Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.
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ABSTRACT:
SUBMITTER: Sudo G
PROVIDER: S-EPMC8486202 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.
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Project description:Macrophages are important regulators of the immune system and are critically involved in the pathophysiology of many diseases. Serum amlyoidosis is a protein misfolding disease which can follow chronic inflammatory conditions. Deposition of fibrils formed from serum amyloid A1 (SAA1) protein occurs systemically and can lead to severe or even fatal outcomes. Macrophages play a critical role in the misfolding and deposition of SAA1-derived fibrils and the role of macrophages in this context has been studied extensively. It is known that SAA1 can bind to some surface receptors on macrophages and it is taken up by the macrophages and metabolized in the lysosomes. On the other hand, the effect of SAA1 on macrophage physiology has been much less investigated so far. Therefore, we aim to investigate the effect of SAA1 on macrophage gene expression by gene microarray analysis. To this end, primary peritoneal macrophages from NMRI mice were treated with endotoxin-free recombinantly expressed full-length mSAA1 for 6 and 24 h and gene expression was analyzed.
2021-07-20 | GSE155278 | GEO
Project description:Uveal melanoma (UM) is the most common primary intraocular cancer in the adult population. Recent studies suggested that the NLRP3 inflammasome could be a therapeutic target for cutaneous melanoma (CM), but the role of NLRP3 in UM remains unknown. Here, we analyzed the NLRP3-IL-1β axis in 5 UM and 4 CM cell lines. Expression of NLRP3 mRNA in UM and CM was low, and expression in UM was lower than in CM (P < 0.001). NLRP3 protein levels were below detection limit for all cell lines. UM exhibited lower baseline IL-1β secretion than CM, especially when compared to the Hs294t cell line (P < 0.05). Bioinformatic analysis of human tumor samples showed that UM has significantly lower expression of NLRP3 and IL-1β compared with CM. In conclusion, our work shows evidence of extremely low NLRP3 expression and IL-1β secretion by melanoma cells and highlight differences between CM and UM.
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Project description:Human serum amyloid A (SAA) is a major acute phase protein and shows a massive increase of concentration in plasma during inflammation. In the current study, we report that recombinant human and mouse SAA1 (rhSAA1 and rmSAA1) have a potent antifungal activity against the major fungal pathogen Candida albicans. rhSAA1 binds to the cell surface of C. albicans and promotes cell aggregation. At high concentrations, rhSAA1 disrupts the membrane integrity and induces rapid cell death of C. albicans. Further investigation demonstrates that rhSAA1 targets on the cell wall adhesin Als3 of C. albicans. Inactivation of ALS3 in C. albicans leads to remarkably decreased cell aggregation and death upon rhSAA1 treatment, implying that Als3 plays a critical role in SAA1 sensing. Moreover, deletion of the ALS3 transcriptional regulators such as AHR1, BCR1, and EFG1 in C. albicans results in a similar effect on cell responses to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling analysis indicates that rhSAA1 has a remarkable impact on the expression of cell wall- and metabolism-related genes in C. albicans. Our finding of the antifungal activity of rhSAA1 against C. albicans expands the function of this protein and would provide new insights into the understanding of the host-Candida interaction during infections.
2019-09-01 | GSE128598 | GEO
Project description:Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1-SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.
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Project description:Several proteins endogenously produced during the process of intestinal wound healing have demonstrated prorestitutive properties. The presence of serum amyloid A1 (SAA1), an acute-phase reactant, within inflamed tissues, where it exerts chemotaxis of phagocytes, is well recognized; however, a putative role in intestinal wound repair has not been described. Herein, we show that SAA1 induces intestinal epithelial cell migration, spreading, and attachment through a formyl peptide receptor 2-dependent mechanism. Induction of the prorestitutive phenotype is concentration and time dependent and is associated with epithelial reactive oxygen species production and alterations in p130 Crk-associated substrate staining. In addition, using a murine model of wound recovery, we provide evidence that SAA1 is dynamically and temporally regulated, and that the elaboration of SAA1 within the wound microenvironment correlates with the influx of SAA1/CD11b coexpressing immune cells and increases in cytokines known to induce SAA expression. Overall, the present work demonstrates an important role for SAA in epithelial wound recovery and provides evidence for a physiological role in the wound environment.
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Project description:Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta (Aβ) senile plaques in patients' brain tissues. Elevated levels of interleukin-1beta (IL-1β) have been identified in cerebrospinal fluid of living AD patients and in animal models of AD. Increased expression of IL-1β and iron accumulation have been identified in microglial cells that cluster around amyloid plaques in AD mouse models and post-mortem brain tissues of AD patients. The goals of this study were to determine the effects of Aβ on the secretion of IL-1β by microglial cells and whether iron status influences this pro-inflammatory signaling cue. Immortalized microglial (IMG) cells were incubated with Aβ with or without iron. qRT-PCR and western blot analyses showed that Aβ induces biosynthesis of IL-1β by IMG cells. IMG cells secrete the mature form of IL-1β in a caspase 1-dependent manner. Incubation with iron provoked a greater pro-inflammatory response. Inhibition of the iron transporter divalent metal transporter 1 protected IMG cells against Aβ-induced inflammation. Potentiation of Aβ-elicited IL-1β induction by iron was also antagonized by ROS inhibitors, supporting the model that divalent metal transporter 1-mediated iron loading and subsequent increase in ROS contribute to the inflammatory effects of Aβ in microglia. Immunoblotting and immunofluorescence microscopy indicate that iron enhances Aβ activation of NF-κB signaling to promote IL-1β synthesis. These results support the hypothesis that Aβ stimulates IL-1β expression by activating NF-κB signaling in microglia cells. Most importantly, iron appears to exacerbate the pro-inflammatory effects of Aβ to increase IL-1β levels.
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Project description:Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood-brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.
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Project description:Diabetes mellitus (DM) is associated with the increased risk of development and the advancement of cholangiocarcinoma (CCA). High glucose levels were previously shown for upregulating interleukin-1β (IL-1β) in CCA cells with unclear functions. The present study, thus, aimed to investigate molecular mechanisms linking DM to CCA progression, with IL-1β hypothesized as a communicating cytokine. CCA cells were cultured in media with normal (5.6 mM) or high (25 mM) glucose, resembling euglycemia and hyperglycemia, respectively. Expressions of IL-1β and IL-1 receptor (IL-1R) in CCA tissues from patients with and without DM were examined using immunohistochemistry. Functional analyses of IL-1β were performed using siRNA and recombinant human IL-1R antagonist (rhIL-1RA), in which Western blots investigated the knockdown efficacy. BALB/c Rag-2-/-Jak3-/- (BRJ) mice were implanted with CCA xenografts to investigate hyperglycemia's effects on CCA growth and the anti-tumor effects of IL-1RA. CCA tumors from patients with hyperglycemia showed significantly higher IL-1β expression than those from non-DM patients, while IL-1β was positively correlated with fasting blood glucose (FBG) levels. CCA cells cultured in high glucose showed increased IL-1β expression, resulting in increased proliferation rates. Suppressing IL-1β signaling by si-IL-1β or rhIL-1RA significantly reduced CCA cell proliferation in vitro. Anakinra, a synthetic IL-1RA, also exerted significant anti-tumor effects in vivo and significantly reversed the effects of hyperglycemia-induced growth in CCA xenografts. IL-1β plays a crucial role in CCA progression in a high-glucose environment. Targeting IL-1β might, then, help improve therapeutic outcomes of CCA in patients with DM and hyperglycemia.
| S-EPMC11292065 | biostudies-literature
Project description:BackgroundCritically ill patients frequently develop muscle atrophy and weakness in the intensive-care-unit setting [intensive care unit-acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute-phase response are major risk factors. We reported earlier that the acute-phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation-induced muscle atrophy.MethodsWe performed cell-based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol-Myers Squibb (BMS)-345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation-induced muscle atrophy and the effects of BMS-345541 treatment.ResultsThe SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll-like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) p65 via TLR2 and TLR4 leading to an increased binding of NF-κB to NF-κB response elements in the promoter region of its target genes resulting in an increased expression of NF-κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF-κB signalling by BMS-345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS-345541 diminished inflammation-induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: -21.2% and BMS-345541: -10.4%; P < 0.05), tibialis anterior (vehicle: -22.7% and BMS-345541: -17.1%; P < 0.05) and soleus (vehicle: -21.1% and BMS-345541: -11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross-sectional area showed that BMS-345541 reduced inflammation-induced atrophy of slow/type I and fast/type II myofibers compared with vehicle-treated septic mice. BMS-345541 reversed the inflammation-induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1.ConclusionsSAA1 activates the TLR2/TLR4//NF-κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF-κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF-κB p65 atrophy pathway could have utility in combatting ICUAW.
| S-EPMC7015249 | biostudies-literature