RESUMEN
Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown. We found that IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal center (GC) T follicular regulatory (Tfr) cells increased the GC response after a first, but not booster, immunization, with an increase in T follicular helper (Tfh) cells, GC B cells, and antigen-specific antibodies, which was reversed upon IL-1 blockade. However, IL-1 signaling is not obligate for GC reactions, as WT and Il1r1-/- mice showed equivalent phenotypes, suggesting that GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2-/- mice did not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulated it, implying that compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn's disease had lower serum IL-1R2. All together, we show that IL-1R2 controls important aspects of innate and adaptive immunity and that IL-1R2 level may contribute to human disease propensity and/or progression.
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Receptores Tipo II de Interleucina-1 , Linfocitos T Colaboradores-Inductores , Humanos , Animales , Ratones , Centro Germinal , Inflamación , Interleucina-1RESUMEN
BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.
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Síndromes de Dolor Regional Complejo , Masculino , Femenino , Humanos , Síndromes de Dolor Regional Complejo/genética , Síndromes de Dolor Regional Complejo/epidemiología , Frecuencia de los Genes , Polimorfismo de Nucleótido Simple/genética , Alelos , Antecedentes GenéticosRESUMEN
BACKGROUND AND AIMS: Atherosclerosis and other cardiovascular diseases (CVD) are well established to be both instigated and worsened by inflammation. Indeed, CANTOS formally proved that targeting the inflammatory cytokine IL-1ß only could reduce both cardiovascular events and death. However, due to the central role of IL-1ß in host defence, blockade increased fatal infections, suggesting targeting key immune mediators over the long natural history of CVD is unsuitable. Thus, discovering alternative mechanisms that generate vascular inflammation may identify more actionable targets. METHODS: We used primary human VSMCs and a combination of biochemical, pharmacological and molecular biological techniques to generate the data. Human carotid atherosclerotic plaques were also assessed histologically. RESULTS: We showed that VSMCs expressed and efficiently processed pro-IL-1ß to the active form after receiving a single stimulus via IL-1R1 or TLR4. Importantly, pro-IL-1ß processing did not utilise inflammasomes or caspases. Unusually, we found that cathepsin C-activated chymase was responsible for cleaving IL-1ß in VSMCs, and provided evidence for chymase expression in cultured VSMCs and in the fibrous cap of human plaques. Chymase also efficiently cleaved and activated recombinant pro-IL-1ß. CONCLUSIONS: Thus, VSMCs are efficient activators of IL-1ß that do not use canonical inflammasomes or caspases. Hence, this alternative pathway could be targeted for long-term treatment of CVDs, as it is not central to everyday host defence.
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Enfermedades Cardiovasculares , Músculo Liso Vascular , Humanos , Interleucina-1beta/metabolismo , Quimasas/metabolismo , Músculo Liso Vascular/metabolismo , Inflamasomas/metabolismo , Células Cultivadas , Inflamación/metabolismo , Caspasas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Miocitos del Músculo Liso/metabolismoRESUMEN
Unabated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1ß production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Ciclo Celular/genética , Interleucina-1beta/genética , Ratones Endogámicos C57BL , Quinasa Tipo Polo 1RESUMEN
AIMS: Atherosclerosis is driven by multiple processes across multiple body systems. For example, the innate immune system drives both atherogenesis and plaque rupture via inflammation, while coronary artery-occluding thrombi formed by the coagulation system cause myocardial infarction and death. However, the interplay between these systems during atherogenesis is understudied. We recently showed that coagulation and immunity are fundamentally linked by the activation of interleukin-1α (IL-1α) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1α [IL-1α thrombin mutant (IL-1αTM)]. METHODS AND RESULTS: Here, we show significantly reduced atherosclerotic plaque formation in IL-1αTM/Apoe-/- mice compared with Apoe-/- and reduced T-cell infiltration. However, IL-1αTM/Apoe-/- plaques have reduced vascular smooth muscle cells, collagen, and fibrous caps, indicative of a more unstable phenotype. Interestingly, the reduced atherogenesis seen with thrombin inhibition was absent in IL-1αTM/Apoe-/- mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1α activation. Finally, bone marrow chimeras show that thrombin-activated IL-1α is derived from both vessel wall and myeloid cells. CONCLUSIONS: Together, we reveal that the atherogenic effect of ongoing coagulation is, in part, mediated via thrombin cleavage of IL-1α. This not only highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1α and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilization.
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Aterosclerosis , Placa Aterosclerótica , Trombina , Animales , Ratones , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/prevención & control , Proliferación Celular , Colágeno/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/metabolismo , Trombina/metabolismoRESUMEN
Interleukin-1 alpha (IL-1α) is a powerful cytokine that drives inflammation and modulates adaptive immunity. Due to these powerful effects, IL-1α is controlled at multiple levels from transcription to cleavage and release from the cell. Genome-wide association studies can identify loci that drive important diseases, although often the functional effect of the variant on phenotype remains unknown or small, with most risk variants in non-coding regions. We find that the common variant rs17561 changes a conserved amino acid in the central region of IL-1α linking the pro piece to the cytokine domain. Using a recall-by-genotype study and whole blood stimulation, we find that minor allele homozygotes release ~50% less IL-1α than the major allele, with IL-1ß release equivalent. IL-1α transcript level was identical between groups, implying a post-transcriptional effect, whilst cleavage of recombinant pro-IL-1α by multiple proteases was also equivalent for both forms. Importantly, transfected macrophages also release less minor allele IL-1α upon inflammasome activation, revealing that reduced secretion is directly caused by the missense amino acid substitution and more minor allele IL-1α was retained within the cell. Thus, rs17561 represents a very common hypomorphic mutation in IL-1α. We believe this novel data will be important for determining the potential contribution of IL-1α to disease and/or physiological processes, for example, by Mendelian randomisation, and may aid patient stratification when considering anti-IL-1 therapies.
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Interleucina-1alfa , Polimorfismo de Nucleótido Simple , Humanos , Interleucina-1alfa/metabolismo , Estudio de Asociación del Genoma Completo , Interleucina-1beta , Inflamación/metabolismo , Células Sanguíneas/metabolismoRESUMEN
Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and VSMC apoptosis occurs in vascular disease, after injury, and in vessel remodeling during development. Although VSMC apoptosis is viewed as silent, recent studies show that apoptotic cells can promote apoptosis-induced compensatory proliferation (AICP), apoptosis-induced apoptosis (AIA), and migration of both local somatic and infiltrating inflammatory cells. However, the effects of VSMC apoptosis on adjacent VSMCs, and their underlying signaling and mechanisms are unknown. We examined the consequences of VSMC apoptosis after activating extrinsic and intrinsic death pathways. VSMCs undergoing apoptosis through Fas/CD95 or the protein kinase inhibitor staurosporine transcriptionally activated interleukin 6 (IL-6) and granulocyte-macrophage colony stimulating factor (GM-CSF), leading to their secretion. Apoptosis induced activation of p38MAPK, JNK, and Akt, but neither p38 and JNK activation nor IL-6 or GM-CSF induction required caspase cleavage. IL-6 induction depended upon p38 activity, while Fas-induced GM-CSF expression required p38 and JNK. Conditioned media from apoptotic VSMCs induced VSMC apoptosis in vitro, and IL-6 and GM-CSF acted as pro-survival factors for AIA. VSMC apoptosis was studied in vivo using SM22α-DTR mice that express the diphtheria toxin receptor in VSMCs only. DT administration induced VSMC apoptosis and VSMC proliferation, and also signficantly induced IL-6 and GM-CSF. We conclude that VSMC apoptosis activates multiple caspase-independent intracellular signaling cascades, leading to release of soluble cytokines involved in regulation of both cell proliferation and apoptosis. VSMC AICP may ameliorate while AIA may amplify the effects of pro-apoptotic stimuli in vessel remodeling and disease.
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Apoptosis/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Interleucina-6/genética , Receptor fas/genética , Animales , Vasos Sanguíneos/crecimiento & desarrollo , Vasos Sanguíneos/metabolismo , Proliferación Celular/genética , Células Cultivadas , Citocinas/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Humanos , MAP Quinasa Quinasa 4/genética , Ratones , Músculo Liso Vascular/citología , Músculo Liso Vascular/fisiología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/fisiología , Proteína Oncogénica v-akt/genética , Transducción de Señal/efectos de los fármacos , Estaurosporina/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1ß are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.
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Membrana Celular/metabolismo , Glicosilfosfatidilinositoles/metabolismo , Interferón gamma/metabolismo , Interleucina-1alfa/metabolismo , Receptores Tipo II de Interleucina-1/metabolismo , Animales , Humanos , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica/fisiología , Transporte de Proteínas/fisiologíaRESUMEN
Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially.
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Envejecimiento/fisiología , Autofagia/efectos de los fármacos , Autofagia/fisiología , Longevidad/fisiología , Neoplasias , Envejecimiento/genética , Animales , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Femenino , Inflamación , Longevidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculos , Fenotipo , Proteína Sequestosoma-1/metabolismo , Piel/patologíaRESUMEN
Cytokines activate or inhibit immune cell behavior and are thus integral to all immune responses. IL-1α and IL-1ß are powerful apical cytokines that instigate multiple downstream processes to affect both innate and adaptive immunity. Multiple studies show that IL-1ß is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing of IL-1ß and its release. However, many alternative mechanisms activate IL-1α and IL-1ß in atypical cell types, and IL-1 function is also important for homeostatic processes that maintain a physiological state. This review focuses on the less studied, yet arguably more interesting biology of IL-1. We detail the production by, and effects of IL-1 on specific innate and adaptive immune cells, report how IL-1 is required for barrier function at multiple sites, and discuss how perturbation of IL-1 pathways can drive disease. Thus, although IL-1 is primarily studied for driving inflammation after release from macrophages, it is clear that it has a multifaceted role that extends far beyond this, with various unconventional effects of IL-1 vital for health. However, much is still unknown, and a detailed understanding of cell-type and context-dependent actions of IL-1 is required to truly understand this enigmatic cytokine, and safely deploy therapeutics for the betterment of human health.
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Interleucina-1/inmunología , Inmunidad Adaptativa/inmunología , Animales , Homeostasis/inmunología , Humanos , Inmunidad Innata/inmunología , Macrófagos/inmunologíaRESUMEN
Our paper, "The Insignificance of Thresholds in Environmental Impact Assessment: An Illustrative Case Study in Canada" received a critique that challenged us on a number of grounds. Namely, that we defame EIA practitioners, that we advocate EIAs to become a scientific enterprise, that we do not recognize the complexity inherent in EIA, and that EIA undergo an independent assessment by regulators. We respond to all of these points, and argue that conflict of interest is an institutional issue (not one of corrupt practitioners), and that we critique the science that forms the basis of evidence in EIA. Further, we show that the complexity and uncertainty in the critique cannot explain the findings from our paper that all cases of impact threshold exceedance were determined to be not significant in EIA. Finally, we compare the significance determinations in proponent reports to final regulator decisions and determine that they are overwhelmingly identical (93-95%). Regulators are financially independent of proponents, but their decisions on significant are heavily dependent on the information and analysis provided by the proponent reports. As regulators rely on these reports, environmental impact assessments must be based on rigorous and transparent analysis.
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Toma de Decisiones , Ambiente , Canadá , IncertidumbreRESUMEN
Pyroptotic cell death during endotoxemia causes death via unknown mechanisms. In this issue of Immunity, Wu et al. (2019) show that T3SS rod proteins or LPS induces inflammasome activation, macrophage pyroptosis, and accompanying tissue factor release, directly connecting inflammation to coagulation.
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Inflamasomas , Piroptosis , Coagulación Sanguínea , Humanos , Inflamación , MacrófagosRESUMEN
Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
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Aterosclerosis/patología , Miocitos del Músculo Liso/patología , Animales , Plasticidad de la Célula , Proliferación Celular , Senescencia Celular , Progresión de la Enfermedad , Matriz Extracelular/fisiología , Humanos , Miocitos del Músculo Liso/fisiología , Fenotipo , Placa Aterosclerótica/patologíaRESUMEN
Interleukin-1 alpha (IL-1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1α in these contexts is unknown. We show IL-1α is activated by caspase-5 or caspase-11 cleavage at a conserved site. Caspase-5 drives cleaved IL-1α release after human macrophage inflammasome activation, while IL-1α secretion from murine macrophages only requires caspase-11, with IL-1ß release needing caspase-11 and caspase-1. Importantly, senescent human cells require caspase-5 for the IL-1α-dependent senescence-associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase-11 for the SASP-driven immune surveillance of senescent cells in vivo. Together, we identify IL-1α as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL-1α is activated during senescence. Thus, targeting caspase-5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.
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Caspasas/metabolismo , Senescencia Celular , Inflamasomas/metabolismo , Inflamación/metabolismo , Interleucina-1alfa/metabolismo , Animales , Células Cultivadas , Femenino , Células HeLa , Humanos , Interleucina-1alfa/análisis , Ratones , Ratones Endogámicos C57BLRESUMEN
Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1α is directly activated by thrombin. Thrombin cleaved pro-IL-1α at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1α on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL-1α in the epidermis. Mice bearing a mutation in the IL-1α thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1α was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.
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Coagulación Sanguínea/fisiología , Sistema Inmunológico/inmunología , Interleucina-1alfa/fisiología , Trombina/fisiología , Inmunidad Adaptativa , Secuencia de Aminoácidos , Animales , Plaquetas/metabolismo , Humanos , Inmunidad Innata , Interleucina-1alfa/genética , Interleucina-1alfa/inmunología , Queratinocitos/metabolismo , Macrófagos/metabolismo , Mamíferos/inmunología , Ratones , Precursores de Proteínas/metabolismo , Selección Genética , Sepsis/inmunología , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Trombopoyesis/inmunología , Cicatrización de Heridas/inmunologíaRESUMEN
Platelets regulate hemostasis and are the key determinants of pathogenic thrombosis following atherosclerotic plaque rupture. Platelets circulate in an inactive state, but become activated in response to damage to the endothelium, which exposes thrombogenic material such as collagen to the blood flow. Activation results in a number of responses, including secretion of soluble bioactive molecules via the release of alpha and dense granules, activation of membrane adhesion receptors, release of microparticles, and externalization of phosphatidylserine. These processes facilitate firm adhesion to sites of injury and the recruitment and activation of other platelets and leukocytes, resulting in aggregation and thrombus formation. Platelet activation drives the hemostatic response, and also contributes to pathogenic thrombus formation. Thus, quantification of platelet-associated responses is key to many pathophysiologically relevant processes. Here we describe protocols for isolating, counting, and activating platelets, and for the rapid quantification of cell surface proteins using flow cytometry.
RESUMEN
Marine debris from the Great Tsunami of 2011 represents a unique transport vector for Japanese species to reach Pacific North America and Hawaii. Here we characterize the invasion risk of invertebrate species associated with tsunami debris using a screening-level risk assessment tool - the Canadian Marine Invasive Screening Tool (CMIST). Higher-risk invertebrate invaders were identified for each of five different ecoregions. Some of these are well-known global invaders, such as the mussel Mytilus galloprovincialis and the ascidian Didemnum vexillum which already have invasion histories in some of the assessed ecoregions, while others like the sea star Asterias amurensis and the shore crab Hemigrapsus sanguineus have yet to invade large portions of the assessed ecoregions but also are recognized global invaders. In general, the probability of invasion was lower for the Gulf of Alaska and Hawaii, in part due to lower climate matches and the availability of other invasion vectors.