Purinergic signaling, DAMPs, and inflammation Di Virgilio, Francesco; Sarti, Alba Clara; Coutinho-Silva, Robson
American Journal of Physiology: Cell Physiology,
2020-May-01, 2020-05-01, 20200501, Letnik:
318, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight actual intruders, and repair ...damage. Several endogenous molecules are used to "signal damage," currently referred to as "alarmins" or "damage-associated molecular patterns" (DAMPs), most being already present within all cells (preformed DAMPs), and thus ready to be released, and others neosynthesized following injury. Over recent years it has become overwhelmingly clear that adenosine 5'-triphosphate (ATP) is a ubiquitous and extremely efficient DAMP (thus promoting inflammation), and its main metabolite, adenosine, is a strong immunosuppressant (thus dampening inflammation). Extracellular ATP ligates and activates the P2 purinergic receptors (P2Rs) and is then degraded by soluble and plasma membrane ecto-nucleotidases to generate adenosine acting at P1 purinergic receptors (P1Rs). Extracellular ATP, P2Rs, ecto-nucleotidases, adenosine, and P1Rs are basic elements of the purinergic signaling network and fundamental pillars of inflammation.
Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) are Gram-negative anaerobic bacteria possessing several virulence factors that make them potential pathogens ...associated with periodontal disease. Periodontal diseases are chronic inflammatory diseases of the oral cavity, including gingivitis and periodontitis. Periodontitis can lead to tooth loss and is considered one of the most prevalent diseases worldwide. P. gingivalis and F. nucleatum possess virulence factors that allow them to survive in hostile environments by selectively modulating the host’s immune-inflammatory response, thereby creating major challenges to host cell survival. Studies have demonstrated that bacterial infection and the host immune responses are involved in the induction of periodontitis. The NLRP3 inflammasome and its effector molecules (IL-1β and caspase-1) play roles in the development of periodontitis. We and others have reported that the purinergic P2X7 receptor plays a role in the modulation of periodontal disease and intracellular pathogen control. Caspase-4/5 (in humans) and caspase-11 (in mice) are important effectors for combating bacterial pathogens via mediation of cell death and IL-1β release. The exact molecular events of the host’s response to these bacteria are not fully understood. Here, we review innate and adaptive immune responses induced by P. gingivalis and F. nucleatum infections and discuss the possibility of manipulations of the immune response as therapeutic strategies. Given the global burden of periodontitis, it is important to develop therapeutic targets for the prophylaxis of periodontopathogen infections.
Physiologic roles of P2 receptors in leukocytes Alberto, Anael Viana Pinto; Ferreira, Natiele Carla da Silva; Bonavita, André Gustavo Calvano ...
Journal of leukocyte biology,
November 2022, Letnik:
112, Številka:
5
Journal Article
Recenzirano
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Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system, purinergic receptors participate ...in innate immunity and in the modulation of the adaptive immune response. In particular, P2 receptors, which respond to extracellular nucleotides, are widely expressed on leukocytes, causing the release of cytokines and chemokines and the formation of inflammatory mediators, and inducing phagocytosis, degranulation, and cell death. The activity of these receptors is regulated by ectonucleotidases—expressed in these same cell types—which regulate the availability of nucleotides in the extracellular environment. In this article, we review the characteristics of the main purinergic receptor subtypes present in the immune system, focusing on the P2 family. In addition, we describe the physiologic roles of the P2 receptors already identified in leukocytes and how they can positively or negatively modulate the development of infectious diseases, inflammation, and pain.
Graphical
Review of how purinergic P2 receptors expression and activation in leukocytes control the development of inflammation, infectious diseases, and pain.
Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and ...related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors-P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.
The role of NOD-like receptors in innate immunity Almeida-da-Silva, Cássio Luiz Coutinho; Savio, Luiz Eduardo Baggio; Coutinho-Silva, Robson ...
Frontiers in immunology,
03/2023, Letnik:
14
Journal Article
Recenzirano
Odprti dostop
The innate immune system in vertebrates and invertebrates relies on conserved receptors and ligands, and pathways that can rapidly initiate the host response against microbial infection and other ...sources of stress and danger. Research into the family of NOD-like receptors (NLRs) has blossomed over the past two decades, with much being learned about the ligands and conditions that stimulate the NLRs and the outcomes of NLR activation in cells and animals. The NLRs play key roles in diverse functions, ranging from transcription of MHC molecules to initiation of inflammation. Some NLRs are activated directly by their ligands, while other ligands may have indirect effects on the NLRs. New findings in coming years will undoubtedly shed more light on molecular details involved in NLR activation, as well as the physiological and immunological outcomes of NLR ligation.
Alteration in microbial populations and metabolism are key events associated with disruption of intestinal homeostasis and immune tolerance during intestinal inflammation. A substantial imbalance in ...bacterial populations in the intestine and their relationships with the host have been observed in patients with inflammatory bowel disease (IBD), believed to be part of an intricate mechanism of triggering and progression of intestinal inflammation. Because elevated numbers of sulfate-reducing bacteria (SRB) have been found in the intestines of patients with IBD, the study of their interaction with intestinal cells and their potential involvement in IBD has been the focus of investigation to better understand the intestinal pathology during IBD, as well as to find new ways to treat the disease. SRB not only directly interact with intestinal epithelial cells during intestinal inflammation but may also promote intestinal damage through generation of hydrogen sulfide at high levels. Herein we review the literature to discuss the various aspects of SRB interaction with host intestinal tissue, focusing on their interaction with intestinal epithelial and immune cells during intestinal inflammation.
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is the protozoan parasite that causes toxoplasmosis, a potentially fatal disease to immunocompromised patients, and which affects approximately 30% of the world's population. Previously, we showed ...that purinergic signaling
the P2X7 receptor contributes to
elimination in macrophages, through reactive oxygen species (ROS) production and lysosome fusion with the parasitophorous vacuole. Moreover, we demonstrated that P2X7 receptor activation promotes the production of anti-parasitic pro-inflammatory cytokines during early
infection
. However, the cascade of signaling events that leads to parasite elimination
P2X7 receptor activation remained to be elucidated. Here, we investigated the cellular pathways involved in
elimination triggered by P2X7 receptor signaling, during early infection in macrophages. We focused on the potential role of the inflammasome, a protein complex that can be co-activated by the P2X7 receptor, and which is involved in the host immune defense against
infection. Using peritoneal and bone marrow-derived macrophages from knockout mice deficient for inflammasome components (NLRP3
, Caspase-1/11
, Caspase-11
), we show that the control of
infection
P2X7 receptor activation by extracellular ATP (eATP) depends on the canonical inflammasome effector caspase-1, but not on caspase-11 (a non-canonical inflammasome effector). Parasite elimination
P2X7 receptor and inflammasome activation was also dependent on ROS generation and pannexin-1 channel. Treatment with eATP increased IL-1β secretion from infected macrophages, and this effect was dependent on the canonical NLRP3 inflammasome. Finally, treatment with recombinant IL-1β promoted parasite elimination
mitochondrial ROS generation (as assessed using Mito-TEMPO). Together, our results support a model where P2X7 receptor activation by eATP inhibits
growth in macrophages by triggering NADPH-oxidase-dependent ROS production, and also by activating a canonical NLRP3 inflammasome, which increases IL-1β production (
caspase-1 activity), leading to mitochondrial ROS generation.
The intestinal microbiota is critical for mammalian immune system development and homeostasis. Sulfate-reducing bacteria (SRB) are part of the normal gut microbiota, but their increased levels may ...contribute to colitis development, likely in association with hydrogen sulfide (H2S) production. Here, we investigated the effects of SRB in the gut immune response in germ-free mice, and in experimental colitis. After 7days of colonization with Desulfovibrio indonesiensis or with a human SRB consortium (from patients with colitis), germ-free mice exhibited alterations in the colonic architecture, with increased cell infiltration in the lamina propria. SRB colonization upregulated the Th17 and Treg profiles of cytokine production/cell activation, in T cells from mesenteric lymph nodes. These alterations were more pronounced in mice colonized with the human SRB consortium, although D. indonesiensis colonization produced higher levels of H2S. Importantly, the colon of C57BL/6 mice with colitis induced by TNBS or oxazolone had increased SRB colonization, and the administration of D. indonesiensis to mice with TNBS-induced colitis clearly exacerbated the alterations in colonic architecture observed in the established disease, and also increased mouse weight loss. We conclude that SRB contribute to immune response activation in the gut and play an important role in colitis development.
Background
During inflammation, stressed or infected cells can release adenosine triphosphate (ATP) to the extracellular medium, which can be hydrolyzed to adenosine by ectonucleotidases such as ...ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5′‐nucleotidase (CD73). The role of CD73 in the modulation of cytokine release by human gingival fibroblasts (HGFs) remains underexplored. Here, we investigated whether CD73‐mediated hydrolysis of extracellular ATP (eATP) could affect interleukin (IL)‐1β‐induced CXCL8 secretion.
Methods
The levels of mRNA expression of adenosine receptors, CD39 and CD73 of periodontitis samples were retrieved from a public database. Moreover, HGF mRNA levels were measured by quantitative reverse transcription‐polymerase chain reaction (RT‐qPCR) after 3, 6, or 24 hours of IL‐1β stimulation. IL‐1β‐induced CXCL8 protein levels were measured after pretreatment with 100‐µM eATP in the presence or absence of CD73 inhibitor. The effect of eATP degradation to adenosine on CXCL8 levels was investigated using agonist and antagonist of adenosine receptors.
Results
Levels of CD39, CD73, and adenosine receptor mRNA were differentially modulated by IL‐1β. ATP pretreatment impaired IL‐1β‐induced CXCL8 secretion and required activation of heme oxygenase‐1 (HO‐1) and phosphorylated adenosine monophosphate‒activated protein kinase (pAMPK). The inhibition of CD73 or the inhibition of adenosine receptors abrogated the ATP effect on CXCL8 secretion.
Conclusions
CD73‐generated adenosine dampens IL‐1β‐induced CXCL8 in HGFs and involves HO‐1 and pAMPK signaling. These results imply that CD73 is a negative regulator of the inflammatory microenvironment, suggesting that this ectoenzyme could be involved in the generation of deficient CXCL8 gradient in chronic inflammation.
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