Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as \u27programmed cell death\u27 have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole

Charcot-Leyden Crystals activate the NLRP3 inflammasome and cause IL-1β inflammation [preprint]

Charcot-Leyden crystals (CLCs) are Galectin-10 protein crystals that can form after eosinophils degranule. CLCs can appear and persist in tissues from patients with eosinophilic disorders, such as asthma, allergic reactions, fungal, and helminthic infections. Despite abundant reports of their occurrence in human disease, the inflammatory potential of CLCs has remained unknown. Here we show that CLCs induce IL-1β release upon their uptake by primary human macrophages in vitro, and that they induce inflammation in vivo in mouse models of acute peritonitis and bronchitis. CLC-induced IL-1β was dependent on NLRP3 and caspase-1, and their instillation in inflammasome reporter mice promoted the assembly of ASC complexes and IL-1β secretion in the lungs. Our findings reveal that CLCs are recognized by the NLRP3 inflammasome, which may sustain inflammation that follows eosinophilic inflammatory processes

PD-L1 is expressed on human platelets and is affected by immune checkpoint therapy

Cancer immunotherapy has been revolutionised by drugs that enhance the ability of the immune system to detect and fight tumors. Immune checkpoint therapies that target the programmed death-1 receptor (PD-1), or its ligand (PD-L1) have shown unprecedented rates of durable clinical responses in patients with various cancer types. However, there is still a large fraction of patients that do not respond to checkpoint inhibitors, and the challenge remains to find cellular and molecular cues that could predict which patients would benefit from these therapies. Using a series of qualitative and quantitative methods we show here that PBMCs and platelets from smokers and patients with head and neck squamous cell carcinoma (HNSCC) or lung cancer express and up-regulate PD-L1 independently of tumor stage. Furthermore, treatment with Atezolizumab, a fully humanised monoclonal antibody against PD-L1, in 4 patients with lung cancer caused a decrease in PD-L1 expression in platelets, which was restored over 20 days. Altogether, our findings reveal the expression of the main therapeutic target in current checkpoint therapies in human platelets and highlight their potential as biomarkers to predict successful therapeutic outcomes

PD-L1 is expressed on human platelets and is affected by immune checkpoint therapy

Cancer immunotherapy has been revolutionised by drugs that enhance the ability of the immune system to detect and fight tumors. Immune checkpoint therapies that target the programmed death-1 receptor (PD-1), or its ligand (PD-L1) have shown unprecedented rates of durable clinical responses in patients with various cancer types. However, there is still a large fraction of patients that do not respond to checkpoint inhibitors, and the challenge remains to find cellular and molecular cues that could predict which patients would benefit from these therapies. Using a series of qualitative and quantitative methods we show here that PBMCs and platelets from smokers and patients with head and neck squamous cell carcinoma (HNSCC) or lung cancer express and up-regulate PD-L1 independently of tumor stage. Furthermore, treatment with Atezolizumab, a fully humanised monoclonal antibody against PD-L1, in 4 patients with lung cancer caused a decrease in PD-L1 expression in platelets, which was restored over 20 days. Altogether, our findings reveal the expression of the main therapeutic target in current checkpoint therapies in human platelets and highlight their potential as biomarkers to predict successful therapeutic outcomes

Augmented plasma microparticles during acute Plasmodium vivax infection

Background: In the last few years, the study of microparticles (MPs) - submicron vesicles released from cells upon activation or apoptosis - has gained growing interest in the field of inflammation and in infectious diseases. Their role in the human malaria parasite Plasmodium vivax remains unexplored. Because acute vivax malaria has been related to pro-inflammatory responses, the main hypothesis investigated in this study was that Plasmodium vivax infection is associated with elevated levels of circulating MPs, which may play a role during acute disease in nonimmune patients. Methods: Plasma MPs were analysed among thirty-seven uncomplicated P. vivax infections from an area of unstable malaria transmission in the Brazilian Amazon. The MP phenotype was analysed by flow cytometry using the classical MP marker, annexin, and fluorochrome-labeled monoclonal antibodies against specific cell surface markers. The frequencies of plasma MPs in P. vivax patients (n = 37) were further compared to malaria-unexposed controls (n = 15) and ovarian carcinoma patients (n = 12), a known MPs-inducing disease non-related to malaria. Results: The frequencies of plasma circulating MPs were markedly increased in P. vivax patients, as compared to healthy age-matched malaria-unexposed controls. Although platelets, erythrocytes and leukocytes were the main cellular sources of MPs during vivax malaria, platelet derived-MPs (PMPs) increased in a linear fashion with the presence of fever at the time of blood collection (b = 0.06, p < 0.0001) and length of acute symptoms (b = 0.36, p < 0.0001). Finally, the results suggest that plasma levels of PMPs diminish as patient experience more episodes of clinical malaria (b = 0.07, p < 0.003). Conclusions: Abundant circulating MPs are present during acute P. vivax infection, and platelet derived-MPs may play a role on the acute inflammatory symptoms of malaria vivax

In silico predicted epitopes from the COOH-terminal extension of cysteine proteinase B inducing distinct immune responses during Leishmania (Leishmania) amazonensis experimental murine infection

<p>Abstract</p> <p>Background</p> <p><it>Leishmania </it>parasites have been reported to interfere and even subvert their host immune responses to enhance their chances of survival and proliferation. Experimental <it>Leishmania </it>infection in mice has been widely used in the identification of specific parasite virulence factors involved in the interaction with the host immune system. Cysteine-proteinase B (CPB) is an important virulence factor in parasites from the <it>Leishmania (Leishmania) mexicana </it>complex: it inhibits lymphocytes Th1 and/or promotes Th2 responses either through proteolytic activity or through epitopes derived from its COOH-terminal extension. In the present study we analyzed the effects of <it>Leishmania (Leishmania) amazonensis </it>CPB COOH-terminal extension-derived peptides on cell cultures from murine strains with distinct levels of susceptibility to infection: BALB/c, highly susceptible, and CBA, mildly resistant.</p> <p>Results</p> <p>Predicted epitopes, obtained by <it>in silico </it>mapping, displayed the ability to induce cell proliferation and expression of cytokines related to Th1 and Th2 responses. Furthermore, we applied <it>in silico </it>simulations to investigate how the MHC/epitopes interactions could be related to the immunomodulatory effects on cytokines, finding evidence that specific interaction patterns can be related to <it>in vitro </it>activities.</p> <p>Conclusions</p> <p>Based on our results, we consider that some peptides from the CPB COOH-terminal extension may influence host immune responses in the murine infection, thus helping <it>Leishmania </it>survival.</p

Growth anomalies on the coral genera Acropora and Porites are strongly associated with host density and human population size across the Indo-Pacific

Growth anomalies (GAs) are common, tumor-like diseases that can cause significant morbidity and decreased fecundity in the major Indo-Pacific reef-building coral genera, Acropora and Porites. GAs are unusually tractable for testing hypotheses about drivers of coral disease because of their pan-Pacific distributions, relatively high occurrence, and unambiguous ease of identification. We modeled multiple disease-environment associations that may underlie the prevalence of Acropora growth anomalies (AGA) (n = 304 surveys) and Porites growth anomalies (PGA) (n = 602 surveys) from across the Indo-Pacific. Nine predictor variables were modeled, including coral host abundance, human population size, and sea surface temperature and ultra-violet radiation anomalies. Prevalence of both AGAs and PGAs were strongly host density-dependent. PGAs additionally showed strong positive associations with human population size. Although this association has been widely posited, this is one of the first broad-scale studies unambiguously linking a coral disease with human population size. These results emphasize that individual coral diseases can show relatively distinct patterns of association with environmental predictors, even in similar diseases (growth anomalies) found on different host genera (Acropora vs. Porites). As human densities and environmental degradation increase globally, the prevalence of coral diseases like PGAs could increase accordingly, halted only perhaps by declines in host density below thresholds required for disease establishment

Molecular and genetic control of plant thermomorphogenesis

Temperature is a major factor governing the distribution and seasonal behaviour of plants. Being sessile, plants are highly responsive to small differences in temperature and adjust their growth and development accordingly. The suite of morphological and architectural changes induced by high ambient temperatures, below the heat-stress range, is collectively called thermomorphogenesis. Understanding the molecular genetic circuitries underlying thermomorphogenesis is particularly relevant in the context of climate change, as this knowledge will be key to rational breeding for thermo-tolerant crop varieties. Until recently, the fundamental mechanisms of temperature perception and signalling remained unknown. Our understanding of temperature signalling is now progressing, mainly by exploiting the model plant Arabidopsis thaliana. The transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4) has emerged as a critical player in regulating phytohormone levels and their activity. To control thermomorphogenesis, multiple regulatory circuits are in place to modulate PIF4 levels, activity and downstream mechanisms. Thermomorphogenesis is integrally governed by various light signalling pathways, the circadian clock, epigenetic mechanisms and chromatin-level regulation. In this Review, we summarize recent progress in the field and discuss how the emerging knowledge in Arabidopsis may be transferred to relevant crop systems