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Vaatwand
Vaatwand
De arteriële vaatwand bestaat uit drie lagen
Intima: binnenste laag bekleed met endotheelcellen. Functie: reguleren van flow, stolling en fibrinolyse.
Media: middelste laag met name bestaand uit glad spierweefsel (SMC) en extracellulaire matrix. Functie: reguleren bloeddruk en kaliber van arterie.
Adventitia: buitenste laag bestaand uit matrix, vasa vasorum en resident immuuncellen. Functie: immuunregulatie en communicatie met autonome zenuwstelsel.
Atherosclerose ontstaat op voorkeursplekken (zie figuur 1A)
Splitsing van arteriën (branch points), o.a. door endotheel dysfunctie en verstoorde flow
Curvatuur met verstoorde flow (bv. korte boog aorta)
Stadia van atherosclerose
Stadia van atherosclerose
Uit het beenmerg ontstaan myeloide cellen uit 'granulocyt-monocyte progenitors' (GMPs), waarij de productietijd doorgaans 1-3 weken is. Er kan geaccelereerde myelopoiese (of wel 'myeloide bias') ontstaan als gevolg van (zie figuur 2):
Acute infecties ('emergency myelopoiesis')
Metabole veranderingen, waaronder (1) cholesterolaccumulatie in GMPs, (2) hyperglycemie en (3) het ontstaan van extramedullaire hematopoiese (o.a. in milt) door hypercholesterolemie.
Functioneel gereprogrammeerde, hyperresponsieve GMPs als gevolg van trained immunity (bv door lipidenrijk dieet) waardoor bij nieuwe (inflammatoire) stimuli eerder geaccelereerde myelopoiese ontstaat.
Ageing, waaronder als gevolg van CHIP (m.n. TET2 en JAK2 mutaties).
CCL2 mobiliseert monocyten uit beenmerg.
Verstoorde flow (bv op artery branch points) leidt tot endotheeldysfunctie en -activatie, verhoogde permeabiliteit, en soms tot directe celschade. Dit leidt tot:
Extravasatie van proatherogene partikels (o.a. LDL-c en Lp(a))
Expressie van adhesiemoleculen (o.a. ICAM1, ICAM2, VCAM2, P-selectine, E-seletine) en chemokines (o.a. CX3CL1-CX3CR1 en CCL5-CCR5) die leiden tot rekrutering, adhesie en vervolgens extravasatie van myeloide cellen.
Gerekruteerde monocyten ontwikkelen zich tot pro-inflammatoire macrofagen onder invloed pro-inflammatoire stimuli in de plaque zoals oxLDL en IFN-gamma uit T-cellen. Deze monocyten/macrofagen kunnen 'lipid-rich' of 'lipid-poor', en hebben diverse functies
Fagocytose van LDL, waarbij een overmaat aan LDL-c al snel leidt tot overschreiding van de capaciteit met vervolgens vorming van schuimcellen (Trem2+ macrofagen) met expressie van genen die betrokken zijn bij cholesterolverwerking (o.a. TREM2 en CD36) (zie figuur 3B).
Productie pro-inflammatoire cytokines uit (o.a. IL-1-beta en TNF-alfa), met name door 'lipid-poor' macrofagen, door NFKB activatie en inflammasoom cq NLRP3 activatie (zie figuur 3C)
Productie chemokines (o.a. CCL2 en IL-8) (zie figuur 3C).
Opruimen van necrotische cellen middels efferocytosis. Dit proces verloopt inefficient, o.a. door 'do-not-eat-me' signalen op apopotische cellen (o.a. CD47)
Macrofagen in de intima zijn tijdens de initiële plaquevorming met name afkomstig van inflammatoire monocyten, maar in een gevorderde plaque voor meer dan 80% afkomstig van in situ proliferatie.
Stadia van atherosclerose
Histological features of the pathogenesis of atherosclerosis. 1) Intimal thickening: the process of atherosclerosis starts when vascular smooth muscle cells (SMCs) and lipids accumulate in the proteoglycan-rich intima. 2) Intimal xanthoma: excess uptake of lipids attracts the first immune cells into the intima, i.e., (lipid laden) macrophages and T cells. 3) Pathological intimal thickening: Immune cells keep accumulating, more and more macrophages obtain a foam cell-rich appearance, and the first extracellular lipid pools become visible. A fibrous cap, composed of vascular SMCs, fibroblasts, and extracellular matrix components, is forming. 4) Fibrous cap atheroma: immune cells keep accumulating and a fibrous cap has fully developed. The core of the plaque shows necrosis and extracellular lipids, often in the form of cholesterol crystals. Calcium deposits form. This area is called the necrotic core. The fibrous cap starts thinning in some areas. 5) Plaque rupture: a fissure in the fibrous cap exposes the thrombogenic contents of the plaque to the blood. A thrombus forms on top of the plaque and may narrow or occlude the arterial lumen. 6) Plaque erosion: thrombus on top of an intact atherosclerotic plaque. The endothelium can be intact, damaged, or absent. Bron
Figuur 2. Myeloide bias / geaccelereerde myelopoiese
Figuur 3. Macrofagen in atherosclerose
A: Rekrutering. B: lipid-rich macrofagen met upregulatie TREM2 en CD36. C: lipid-poor macrofagen met productie pro-inflammatoire cytokines
Pathogenese van atherosclerose
The pathogenesis of atherosclerosis. Atherosclerotic plaques mostly form at sites where laminar flow is disturbed. This, combined with oxidative stress, results in the activation of the endothelium, increased permeability, upregulation of leukocyte adhesion molecules, and leukocyte recruitment (1). Circulating lipids, especially LDL cholesterol, start entering the subendothelial space, where LDL, containing apolipoprotein B, becomes modified (2), thereby eliciting danger signals that are recognized by the innate immune system present in the arterial intima. Monocytes, macrophages, and neutrophils start releasing chemokines and cytokines (3), and neutrophils form neutrophil extracellular traps (NETs) (4), resulting in a perpetuating cascade of leukocyte recruitment and activation. This includes the recruitment of adaptive immune cells, including T and B cells, into the plaque (5). Vascular smooth muscle cells (VSMCs) and fibroblasts migrate from the media to form the fibrous cap (6). Activated VSMCs and fibroblasts produce collagen and other extracellular matrix molecules, further contributing to fibrous cap formation (7). Macrophages and VSMCs phagocytose excessive lipids and become foam cells (8). Excess lipid uptake, as well as inadequate efferocytosis, results in cell death and extracellular lipid accumulation in the plaque as well as the formation of cholesterol crystals: the beginning of the necrotic core (9). In parallel, antigens, including peptides from apolipoprotein B, are being presented in the immunological synapse [major histocompatibility complex (MHC)-T-cell receptor (TCR) complex and costimulatory/coinhibitory complex] by antigen-presenting cells, resulting in antigen-specific T-cell proliferation and cytokine production (10) and antibody production (IgG) by B cells (11). Innate type B cells, producing only antioxidation-specific epitope (OSE) IgM antibodies, are also found in the plaque (12). Ultimately, the chronic inflammatory response induces breakdown of the fibrous cap (13) and development of a necrotic core (14), resulting in plaque rupture and atherothrombosis (15). During atherosclerosis, the adventitia and perivascular adipose tissue, originally house resident immune cells, become inhabited by a plethora of immune cells, similar to those in the atherosclerotic plaque, thereby actively contributing to vascular inflammation and progression of atherosclerosis (16). Bron
Myeloide cellen
Myeloide cellen
Myeloid cell subsets in atherosclerosis. The immune landscape of the human carotid atherosclerotic plaque has been recently resolved through the use of single-cell biology techniques. Fourteen distinct myeloid populations were identified; a mast cell population (TPSB2, TPSAB1, and MS4A2), a plasmacytoid dendritic cell population (pDC; CLEC4C, IRF7, IRF8, JCHAIN, and LILRA4), 4 conventional DCs (cDCs), and 7 monocytes/macrophage populations. The main subsets are further downstream classified as pro (red)- or anti (blue)-atherogenic role through analysis of the top differentially expressed genes (DEGs). All cDC populations express HLA-DR genes as well as individual gene signatures; cDC2 cells express CD1C, CLEC10A, and FCER1A, while the cDC1 cluster is identified by the expression ofCLEC9A, IRF8, and SNX3. Mature cDC2s are recognized by high expression of the egress chemokine receptorCCR7- and CCR7-specific chemokines (CCL17,CCL19, andCCL22) as well as maturation genes (LAMP3 and IDO1) and immunoregulatory genes such as CD40, CD200, TNFRSF4 (gene coding OX40), and CD274 (gene coding PDL-1). Finally, a small population of AXL and SIGLEC6 (AS) expressing DC is identified; however, its role in disease is still unknown. Monocytes/ macrophages in the human carotid plaque segregate into 7 distinct populations. S100A8/IL1B1 and S100A8/IL1Bpopulations have a less differentiated phenotype compared to the rest of the macrophages found in the plaque and are sometimes referred to as monocytes or mono-macs. They share a high expression of calgranulins S100A8/S1009/S10012. However, they differ in other genes: cluster S100A8/IL1Bis characterized by a stress response gene signature including several heat shock protein genes coding for heat shock protein (HSP)70 (HSPA1A, HSPA1B, HSP6), HSP90 (HSP90AA1), and HSP40 (DNAJB1). The S100A8/IL1B1 cluster is characterized by expression of genes in the inflammasome pathway: IL1B, NLRP3, and CASP4; proinflammatory cytokine/chemokines: TNF, CCL3, CCL4, CCL3L3, CCL4L2, and CCL20; proinflammatory transcription factors:CEBPB and NFKB1; and receptors: TLR2 and TREM1. In line with a highly inflammatory profile, S100A8/IL1B1 expresses senescence genes (CDKN1, PTGER2, and PTGS2) as well as genes involved in cell death, proliferation, and survival (BCL2A1, BTG1, and GOS2). This suggests S100A8/IL1B1 as a terminal and a highly proinflammatory and proatherogenic cluster. The IL101/TNAIP31 population shares a high IL1B expression with S100A8/IL1B1; however, in addition to expressing proinflammatory genes, IL101/TNAIP31 has a clear anti-inflammatory signature, exclusively expressing the anti-inflammatory cytokine IL10, the NF-κB inhibitor TNFAIP3 and the anti-inflammatory receptor GPR183, highlighting the potential role of this subset in rebalancing the immune responses in plaques. C1Q and HMOX1 clusters are defined by high expression of the complement C1q family (C1QA, C1QB, and C1QC), genes common to resident-like macrophages, suggesting an homeostatic role in the atherosclerotic plaque environment. TREM2hi and PLIN2hi/ TREM1hi are 2 distinct lipid-associated macrophage (LAM) clusters. They share a lipid-associated transcriptional signature including fatty acid-binding proteins (FABP4 and FABP5) and lipid scavenger receptors (CD3 and MARCO). TREM2hi expresses genes involved in regulating cholesterol metabolism, transport, and efflux (ANXA2, APOC1, APOC2, APOE, CYP27A1, and NR1H3, the gene encoding the transcription factor LXRa) as well as genes involved in lysosomal degradation (LIPA, LGMN, and PSAP) and a strong antioxidant signature related to metallothionein MT1G, MT1X, MT1E, and MT1F, a group of antioxidant proteins expressed in response to injury. This gene signature along with a lack of inflammatory genes suggests TREM2hi to be highly competent in lipid uptake, cholesterol metabolism, and efflux. PLIN2hi/TREM1hi macrophages express a high level of the perilipin gene PLIN2, a bona fide lipid storage and foam cells marker, coding for a structural component of lipid droplets. Unlike TREM2hi cluster, PLIN2hi/TREM1hi lacks expression of genes involved in lysosomal degradation and most genes involved in cholesterol efflux suggesting that the lipid uptake is not paralleled by an increase in efflux leading to marked cholesterol storage. PLIN2hi/TREM1hi expresses genes in the inflammatory and inflammasome pathway TREM1, TNF,CEBPB,OLR1, and IL1Bas well as genes involved in endoplasmic reticulum unfolding protein response such asATF3, CALR, ACADVL, HSPA5, and HSP90B1 and genes involved in apoptosis, antiproliferation and survival such as GOS2, BTG1, BCL2A1, IER3, EGR1, BNIP3L, and MCL1. Finally, the phenotype of TREM1 foam cells is completed by a high chemokine secretory signature, PLIN2hi/TREM1hi cells selectively expressCCL2 andCCL7 in the plaque as well as high levels ofCCL20,CXCL3,CXCL2, and CXCL8. This strong and specific chemokine signature suggests that these inflammatory foam cells might propagate the disease by playing a major role in the recruitment of immune cells to the plaque. Bron
Inflammasoom
Inflammasoom
NOD-like receptors (NLRs) zijn sensoren in het cytoplasma die reageren op een infectie of celschade.
Het inflammasoom in macrofagen betreft een intracellulair multi-eiwit complex dat verschillende pathogen-associated molecular patterns (PAMPs) en damage-associated molecular patterns (DAMPs) herkent.
In de context van atherosclerose wordt NLRP3 ('cryoporine') in macrofagen geactiveerd door (1) binding van oxidized LDL aan TLR4, (2) herkenning van NETs, (3) herkenning van cholesterolkristallen of (4) herkenning van ATP uit stervende cellen. TET2 CHIP kan NLRP3 activatie boosten.
Na herkenning volgt activatie van NLRP3 door oligomerisatie. Hierdoor ontstaat een platform voor recruitment en activatie van caspase-1, wat op zijn beurt pro-IL-1B geknipt waarna IL-1-beta geproduceerd wordt. Ook wordt IL-18 geproduceerd.
Inflammasomen kunnen ook celdood via pyroptose induceren.
Colchicine kan de vorming (oligomerisatie) van NLRP3 remmen doordat het een microtubulaire remmer is.
Cellular damage activates the NLRP3 inflammasome to produce pro-inflammatory cytokines. The LRR domain of NLRP3 associates with chaperones (HSP90 and SGT1) that prevent NLRP3 activation. Damage to cells caused by bacterial pore-forming toxins or activation of the P2X7 receptor by extracellular ATP allows efflux of K+ ions from the cell; this may dissociate these chaperones from NLRP3 and induce multiple NLRP3 molecules to aggregate through interactions of their NOD domains (also called the NACHT domain). Reactive oxygen intermediates (ROS) and disruption of lysosomes also can activate NLRP3 (see text). The aggregated NLRP3 conformation brings multiple NLRP3 pyrin domains into close proximity, which then interact with the pyrin domains of the adaptor protein ASC (PYCARD). This conformation aggregates the ASC CARD domains, which in turn aggregate the CARD domains of pro-caspase 1. This aggregation of procaspase 1 induces proteolytic cleavage of itself to form the active caspase 1, which cleaves the immature forms of pro-inflammatory cytokines, releasing the mature cytokines that are then secreted.
The inflammasome is composed of several filamentous protein polymers created byaggregated CARD and pyrin domains. Schematic interpretation of NLRP3 inflammasome assembly. In this model, CARD regions of ASC and caspase 1 aggregate into a filamentous structure. The adaptor ASC translatesaggregation of NLRP3 into aggregation of pro-caspase 1.
Checkpoints in atherosclerose
Checkpoints in atherosclerose
The immunological synapse in atherosclerosis. Antigen-presenting cells (APCs) can mediate T-cell activation, proliferation, and polarization through three different signals. Signal 1 consists of presentation of atherosclerosis-relevant antigens, including heat-shock protein (HSP)60, apolipoprotein (apo)B, malondialdehyde (MDA)-LDL, phosphocholine (PC), aldehyde dehydrogenase (ALDH)4A1, on major histocompatibility complex (MHC) molecules on APCs to the T-cell receptor (TCR) on T cells. In addition to antigen recognition, T cells also require costimulation for subsequent activation. Such costimulatory signals are provided by immune checkpoint proteins, which alternatively may also elicit inhibitory signals that can halt T-cell proliferation or induce skewing toward anti-inflammatory immune cells. A third signal is provided by cytokines present in the atherosclerotic microenvironment, which can influence T-cell polarization toward for instance IFNc-secreting Th1 cell Bron
Rol van T-cellen in atherosclerose
Rol van T-cellen in atherosclerose
Lymphoid cell subsets in atherosclerotis
Lymphoid cells in the atherosclerotic plaque can be broadly divided into CD4 T cells, CD8 T cells, B cells, and natural killer (NK) cells; however single-cell sequencing has revealed a variety of subsets within these lineages. Apart from regulatory T cells (Tregs), CD4 T cells are not subdivided along the classic T-helper paradigm but appear to exist in various stages of activation; ranging from a naïvelike central memory CD4 T cells (TCM) to CD40L1 effector memory CD4 T cells (TEM) and, ultimately, exhausted CD4 T cells. CD8 T cells consist of highly cytotoxic effector cells (TEFF), which express cytolysis-related genes encoding granzyme B (GZMB), granulysin (GNLY), and perforin (PRF1) and contain terminal differentiation (GZMK) or senescence-associated subsets (TEM and CD8 IFN response). Mucosal-associated invariant T cells (MAIT) and NK cells make up minor populations, although 2 distinct NK cell populations can be distinguished, with one population bearing markers of cytolysis (FCGR3A1 NK cells) and a second population expressing chemotaxis-related genes (XCL11 NK). Finally, B cells make up about 10% of the lymphocyte population in the atherosclerotic plaque but present various stages of B-cell maturation, including unswitched IgM1 B cells, class-switched (IgG1) memory B cells, and antibody-producing plasma cells. The enigmatic age-associated B cell is defined by coexpression of genes translating CD11c (ITGAX), CD11b (ITGAM), and T-bet (TBX21). Bron
a | Naive CD4+ T helper (TH) cells are primed in secondary lymphoid organs. TH cells acquire the complete phenotype of effector T (Teff) cells or regulatory T (Treg) cells after encountering antigenic peptides from apolipoprotein B (ApoB) presented by antigen-presenting cells (APCs). APCs take up and process oxidized LDL (OxLDL), migrate to the draining lymph node and present peptides from ApoB on major histocompatibility complex (MHC) class II molecules. Naive T cells recognize this complex through their specific T cell receptors (TCRs). Co-stimulatory molecules induce T cells to express transcription factors that favour the differentiation into distinct TH phenotypes. Homing receptors promote T cell migration to atherosclerotic lesions, where they secrete effector cytokines. b,c | CD4+ T cells can act in a pro-atherogenic or atheroprotective manner. Atherosclerotic lesions contain TH1, TH2, TH9, TH17, TH22, Treg, type 1 regulatory T (Tr1) cells and follicular helper T (TFH) cells. Treg cells can convert to ‘exTreg cells’ (dashed arrows), losing expression of CD25 and forkhead box protein P3 (FOXP3) and acquiring properties of other TH cell phenotypes such as TH1, TH17 and TFH. Instability of FOXP3 expression triggers the formation of antigen-specific, but dysfunctional, partially non-protective exTreg cells. AHR, aryl hydrocarbon receptor; BCL-6, B cell lymphoma 6; CCR5, CC-chemokine receptor 5; CXCR3, CXC-chemokine receptor 3; EC, endothelial cell; G-CSF, granulocyte colony-stimulating factor; GATA3, GATA-binding factor 3; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFNγ, interferon-γ; LAG3, lymphocyte activation gene 3 protein; OxPL, oxidized phospholipid; PL, phospholipid; RORγt, nuclear receptor RORγt; T-bet, T-box transcription factor TBX21; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; VCAM1; vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell. Bron
T-cel exhaustion
Progressive differentiation of exhausted T cell (Tex cell) lineage subsets. Naive antigen-specific CD8+ T cells are activated in response to immune challenge and develop into effector cells that proceed to differentiate along one of several pathways. In response to acute infection, activated CD8+ T cells can differentiate into memory precursor (Mem pre) cells or short-lived effector cells (SLECs). SLECs are characterized by high expression of TBET, BLIMP1, and KLRG1 and by low expression of IL7rα. In contrast, Mem pre cells express TCF1, EOMES, and IL7rα. Effective CD8+ T cell responses promote pathogen clearance and a resulting decrease in antigen load. As the immune challenge resolves, SLECs are eliminated by apoptosis, while Mem pre cells survive and form a long-lived memory pool. In response to rechallenge, memory cells quickly differentiate into effector cells that rapidly clear the infection while self-renewing to maintain the memory population. In contrast, during chronic infection, CD8+ T cells differentiate into a Tex precursor (Tex pre) population characterized by expression of TCF1, EOMES, and TOX. As the cells are continually challenged, they progress to a Tex progenitor (Tex prog) subset with the capacity to self-renew and give rise to intermediate exhausted (Tex int) cells. The Tex int cells lose expression of TCF1 and ultimately differentiate into terminally exhausted (Tex term) cells with poor cytokine production and high expression of inhibitory receptors.Bron
Bevindingen
Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self (bron)
Plaque T cells are in an activated state as reflected by presence of clonal CD4+ and CD8+ T-cells, as well as CD69+ T-cells (reflecting activated state).
Plaques contain T cells that react to viruses. Plaque T cells with viral specificities may be reacting to self-antigens that have similar homologies to viral epitopes, a process known as molecular mimicry. Alternatively, these virus-specific T cells found in atherosclerotic plaque may be activated by cytokines and not by viral-specific engagement—a process commonly referred to as bystander activation that is commonly triggered by interferons such as type I IFN (eg, IFNG), IL-15, and IL-18.
It is plausible that both TCR-dependent and TCR-independent activation of plaque T cells act synergistically to mediate atherosclerotic progression and plaque rupture.
Cross talk between macrophages and T cells is required for T-cell activation. In plaques, significant ligand-receptor relationships between macrophages and T cells are found, some of which have been shown to modulate T-cell activation
Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis (Mulholland, 2025) (bron)
PD-1 is expressed on aortic IFNγ-producing T cells and that the majority of the PD-1+ T cells in the atherosclerotic aorta display a polyfunctional progenitor exhausted state.
Blocking PD-1 signaling increased T cell cytokine production, formation of lymphocyte foci in the plaque and accumulation of late exhausted PD-1+ Tim3+ T cells.
Human circulating PD-1+ T cells were enriched for cells capable of producing IFNγ upon restimulation and were associated with presence of subclinical atherosclerosis.
PD-1 blockade may promote expression of Cxcl5 in plaques and drive neutrophil accumulation.
Llevels of T cells with recent TCR signaling (Nur77 positivity) were relatively low in the atherosclerotic aorta
Expanded cells found in the plaque may not only be locally proliferating, plaque autoreactive T cells but could also be pathogen-specific T cells that expanded peripherally and then were recruited to the lesion
PD-1+ T cells produce elevated levels of IFNγ upon TCR-driven or cytokine-mediated activation compared to PD-1− counterparts. the observation that PD-1+ T cells are responsive to cytokine activation provides an antigen-independent mechanism whereby plaque T cells may be activated and contribute to disease formation
Vragen
Weinig PD1 expressie in carotiden
Meer PD-1+ CD8+ T-cellen geassocieerd met subklinische atherosclerose
Tumor-specifieke T-cellen gerekruteerd naar tumor na anti-PD1, maar ook naar plaque?
IFN-gamma perifeer goede marker? Increased plasma levels of CXCL9 and CXCL10 after anti-PD-1 therapy?
Cellular senescence
Cellular senescence
Cel cyclus
Cel cyclus
Een eukaryote celcyclus bestaat uit vier verschillende fasen
G1: celgroei
S: DNA replicatie
G2: voorbereiding op mitose
M: mitose en cytokinese
Vanuit de G1 fase kunnen cellen ook overgaan in de G0 fase of rustfase waarin geen deling meer plaatsvindt
Cyclin-dependent kinases (CDKs) kunnen binden aan cyclin waardoor een cyclin-dependent kinase complex (CDKC) ontstaat. Dit soort eiwitcomplexen kunnen betrokken zijn bij celcyclus progressie en regulatie.
CDK inhibitors kunnen de celcyclus remmen door de vorming van CDKCs te remmen.
Senescence
Senescence
Senescence is een vorm van stabiele 'cell fate' (lotbepaling; i.t.t. quiescence of terminale differentiatie) en wordt gezien als (stress)reactie op interne of externe stressoren
Senescence is een irreversibel celcyclusarrest met resistentie voor apoptose als gevolg van upregulatie van pro-survival pathways (senescent cell anti-apoptotic pathways, SCAP) en downregulatie van apoptotische mediators.
De stressoren die kunnen leiden tot senescence zijn onder andere:
Replicatieve stress gepaard met telomeer verkorting
Activatie DNA schade pathways
Epigenetische veranderingen
Oxidatieve stress
Mitochondriële dysfunctie
Radiatie
Inductie van oncogenen
Mechanische of shear stress
Door deze stressoren worden de p53-Cdkn1a (p21=p21Cip1/Wa f) en retinoblastoma-Cdkn2a (p16=p16Ink4a ) pathways geactiveerd. P16 (gen: CDKN2A) en p21 (gen: CDKN1A) zijn cyclin-dependent kinase inhibitors die leiden tot G1/S celcyclus blokkade.
Evolutionaire functies van senescence zijn onder andere:
Het uitgroeien van embryonale structuren sturen, zoals extremiteiten.
Tissue remodeling
Balans bewaken tussen genezing en fibrose in regeneratieve processen (bijvoorbeeld wonden)
Tumorsuppressie
Verschillende stressoren kunnen tot unieke senescent populaties leiden (senotypes), elk met eigen eigenschappen (o.a. distincte transcriptionele, spatiële en functioneel identiteiten). Senescente cellen zijn derhalve zeer heterogeen. Het fenotype wordt o.a. bepaald door:
Type stressor/trigger
Type cel
Weefsel en omgeving
Tijd sinds senescence initiatie
Senescence kan i.p.v. een 'single state' eigenlijk beter geconceptualiseerd worden als een 'trajectory' of 'latent continuum' waarin cellen eigenschappen accumuleren, zoals chromatine reorganisatie, transcriptionele reprogrammering, mitochondriële dysfunctie en SASP activiteit (bron).
Er is geen universele biomarker. Senescente cellen kunnen worden gekenmerkt door (zie ook Tabel hiernaast)
SA-β-gal activiteit (lysosomale verandering)
Verhoogde p16 en p21 expressie
Verkorte telomeren (nucleaire verandering)
Epigenetische veranderingen zoals verlies van histone H3 Lys9 trimethylatie (H4K9me3) en lamin B1 downregulatie.
Dysregulatie van oxidatieve fosforylering
Senescencte cellen zijn zeldzaam (somds <0.5% van populatie) en fragiel (o.a. gevoelig voor mechanische stress) waardoor ze moeilijk te isoleren, dissociëren en profileren zijn. Door de heterogeniteit clusteren ze slecht samen in principal component analysis (bron).
Senescence-associated secretory phenotype (SASP)
Senescence-associated secretory phenotype (SASP)
Als cellen senescent worden, dan kunnen ze verschillende SASP factoren uitscheiden, ofwel via directe uitscheiding of via exosomes, die doorgaans leiden tot lokale en systemische inflammatie:
Cytokines
Matric metalloproteinases
MicroRNAs
Chemokines (o.a. IL-1, IL-8, TNF-alfa)
Groeifactoren
Metabolieten
SASP chemokines kunnen immuuncellen rekruteren zoals macrofagen, neutrofielen en T-cellen.
SASP factoren kunnen op zichzelf weer accumulatatie van senescente cellen stimuleren (feed forward loop), waardoor een chronisch inflammatoir milieu ontstaat (zie Figuur hiernaast).
Er zijn dus primair en secundair geïnduceerde senescente cellen.
Cellular senescence is induced following exposure to an initial stress. The resulting senescent cells produce a SASP that can potentiate further senescent cell accumulation and impair clearance. In turn, the SASP can be amplified, eliciting an environment of chronic inflammation and additional senescence-inducing stressors that drive a feed-forward cycle of senescent cell accumulation.Bron
Senolytica
Senolytica
Senescence kan geremd worden door senomorfe compounds (remming van SASP signalen) of senolytica (elimineren van senescente cellen)
Voorbeelden zijn
Dasatinib (Src kinase inhibitor) en quercetin (D+Q)
Fisetin (een flavonoide)
BCL-2 family inhibitors (o.a. navitoclax)
Senescence en atherosclerose
Senescence en atherosclerose
Atherosclerotische plaques bevatten veel senescente endotheelcellen (foamy-like endotheelcellen), vascular smooth muscle cells (VSMCs) en macrofagen.
Endotheelcel senescence leidt tot verminderde NO productie, verhoogde productie van inflammatoire cytokines en adhesiemoleculen.
Senescente T cellen kunnen accumuleren in obees vetweefsel en bijdragen aan systemische inflammatie.
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