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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.

We examined the involvement of the P2 × 7 receptor and the canonical and noncanonical inflammasomes in the control of single-species or dual-species infection by the periodontal bacteria Porphyromonas gingivalis and Fusobacterium nucleatum in cells and mice. Stimulation of the P2 × 7 receptor leads to activation of the canonical NLRP3 inflammasome and activation of caspase-1, which leads to cleavage of pro-IL-1β to IL-1β, a key cytokine in the host inflammatory response in periodontal disease. The non-canonical inflammasome pathway involves caspase-11. Thus, wildtype (WT), P2 × 7-/-, caspase-11-/- and caspase-1/11-/- mice were co-infected with both bacterial species. In parallel, bone marrow-derived macrophages (BMDMs) from WT mice and the different knockout mice were infected with P. gingivalis and/or F. nucleatum, and treated or not with extracellular ATP, which is recognized by P2 × 7. F. nucleatum infection alone promoted secretion of IL-1β in BMDMs. Conversely, the canonical pathway involving P2 × 7 and caspase-1 was necessary for secretion of IL-1β in BMDMs infected with P. gingivalis and in the mandible of mice coinfected with P. gingivalis and F. nucleatum. The P2 × 7 pathway can limit bacterial load in single-species and dual-species infection with P. gingivalis and F. nucleatum in BMDMs and in mice. The non-canonical pathway involving caspase-11 was required for secretion of IL-1β induced by F. nucleatum infection in BMDMs, without treatment with ATP. Caspase-11 was also required for induction of cell death during infection with F. nucleatum and contributed to limiting bacterial load during F. nucleatum infection in BMDMs and in the gingival tissue of mice coinfected with P. gingivalis and F. nucleatum. Together, these data suggest that the P2 × 7-caspase-1 and caspase-11 pathways are involved in the immune response against infection by P. gingivalis and F. nucleatum, respectively.

The digestive system is a fundamental topic in biological science teaching. Despite its importance, the level of students' knowledge on the topic appears to differ from recommended levels at several educational grades. Their knowledge also seems to be resistant to change; therefore, this discrepancy may be viewed as an epistemological obstacle to teaching scientifically updated concepts related to the digestive system. Didactic-pedagogical resources are important tools for overcoming such difficulties. The present study was intended to analyse the use of a practical activity as a possible didactic resource to help (re)construct concepts regarding human digestive physiology and to amplify the conceptual profile of undergraduate students. Data collection was performed using questionnaires and semi-structured interviews to assess students' knowledge of the digestive system before and after participating in the practical activity. Qualitative data analysis revealed that previous knowledge was partially aligned with that described in the literature, suggesting a possible epistemological obstacle to teaching and learning scientific concepts. Participation in the activity not only contributed to better understanding of general aspects of the digestive system but also appeared to help overcome possible epistemological obstacles, including the role of the intestine.

BackgroundDuring 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.MethodsThe 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.ResultsLevels 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.ConclusionsCD73-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.

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.

Toxoplasmosis is a globally significant disease that poses a severe threat to immunocompromised individuals, especially in Brazil, where a high prevalence of virulent and atypical strains of Toxoplasma gondii is observed. In 1998, the EGS strain, exhibiting a unique infection phenotype, was isolated in Brazil, adding to the complexity of strain diversity. The P2X7 receptor is critical in inflammation and controlling intracellular microorganisms such as T. gondii. However, its genetic variability can result in receptor dysfunction, potentially worsening susceptibility. This study investigates the role of the P2X7 receptor during acute infection induced by the EGS atypical strain, offering insight into the mechanisms of T. gondii infection in this context. We infected the female C57BL/6 (WT) or P2X7 knockout (P2X7−/−) by gavage. The EGS infection causes intestinal inflammation. The P2X7−/− mice presented higher parasite load in the intestine, spleen, and liver. The absence of the P2X7 receptor disrupts inflammatory cell balance by reducing NLRP3, IL-1β, and Foxp3 expression while increasing IFN-γ expression and production in the intestine. In the liver, P2X7-/- animals demonstrate diminished inflammatory infiltrate within the portal and lobular regions concurrent with an enlargement of the spleen. In conclusion, the infection of mice with the EGS strain elicited immune alterations, leading to acute inflammation and cytokine dysregulation, while the P2X7 receptor conferred protection against parasitic proliferation across multiple organs. [ABSTRACT FROM AUTHOR]

BackgroundFusobacterium nucleatum is a Gram-negative anaerobic bacterium associated with periodontal disease. Some oral bacteria, like Porphyromonas gingivalis, evade the host immune response by inhibiting inflammation. On the other hand, F. nucleatum triggers inflammasome activation and release of danger-associated molecular patterns (DAMPs) in infected gingival epithelial cells.MethodsIn this study, we characterized the pro-inflammatory response to F. nucleatum oral infection in BALB/c mice. Western blots and ELISA were used to measure cytokine and DAMP (HMGB1) levels in the oral cavity after infection. Histology and flow cytometry were used to observe recruitment of immune cells to infected tissue and pathology.ResultsOur results show increased expression and production of pro-inflammatory cytokines during infection. Furthermore, we observe that F. nucleatum infection leads to recruitment of macrophages in different tissues of the oral cavity. Infection also contributes to osteoclast recruitment, which could be involved in the observed bone resorption.ConclusionsOverall, our findings suggest that F. nucleatum infection rapidly induces inflammation, release of DAMPs, and macrophage infiltration in gingival tissues and suggest that osteoclasts may drive bone resorption at early stages of the inflammatory process.

Chlamydiae are obligate intracellular bacterial pathogens, and as such are sensitive to alterations in the cellular physiology of their hosts. Chlamydial infections often cause pathologic consequences due to prolonged localized inflammation. Considerable advances have been made in the last few years regarding our understanding of how two key inflammation-associated signaling pathways influence the biology of Chlamydia infections: inflammation regulating purinergic signaling pathways significantly impact intracellular chlamydial development, and inflammasome activation modulates both chlamydial growth and infection mediated pro-inflammatory cytokine production. We review here elements of both pathways, presenting the latest developments contributing to our understanding of how chlamydial infections are influenced by inflammasomes and purinergic signaling.

Despite recent advances unraveling mechanisms of host-pathogen interactions in innate immunity, the participation of purinergic signaling in infection-driven inflammation remains an emerging research field with many unanswered questions. As one of the most-studied oral pathogens, Porphyromonas gingivalis is considered as a keystone pathogen with a central role in development of periodontal disease. This pathogen needs to evade immune-mediated defense mechanisms and tolerate inflammation in order to survive in the host. In this review, we summarize evidence showing that purinergic signaling modulates P. gingivalis survival and cellular immune responses, and discuss the role played by inflammasome activation and cell death during P. gingivalis infection.

Schistosomiasis is an intravascular infectious disease that impacts over 200 million people globally. In its chronic stage, it leads to mesenteric inflammation with significant involvement of monocytes/macrophages. Endothelial cells lining the vessel lumens play a crucial role, and mount of evidence links this disease to a downregulation of endoprotective cell signaling favoring a primed and proinflammatory endothelial cell phenotype and therefore the loss of immunovascular homeostasis. One hallmark of infectious and inflammatory conditions is the release of nucleotides into the extracellular milieu, which, in turn, act as innate messengers, activating purinergic receptors and triggering cell-to-cell communication. ATP influences the progression of various diseases through P2X and P2Y purinergic receptor subtypes. Among these receptors, P2Y2 (P2Y2R) and P2X7 (P2X7R) receptors stand out, known for their roles in inflammation. However, their specific role in schistosomiasis has remained largely unexplored. Therefore, we hypothesized that endothelial P2Y2R and P2X7R could contribute to monocyte adhesion to mesenteric endothelial cells in schistosomiasis. Using a preclinical murine model of schistosomiasis associated with endothelial dysfunction and age-matched control mice, we showed that endothelial P2Y2R and P2X7R activation increased monocyte adhesion to cultured primary endothelial cells in both groups. However, a distinct upregulation of endothelial P2Y2R-driven canonical Ca2+ signaling was observed in the infected group, amplifying adhesion. In the control group, the coactivation of endothelial P2Y2R and P2X7R did not alter the maximal monocyte adhesion induced by each receptor individually. However, in the infected group, this coactivation induced a distinct upregulation of P2Y2R-P2X7R-driven canonical signaling, IL-1β release, and VCAM-1 expression, with underlying mechanisms involving inflammasome and NF-κB signaling. Therefore, current data suggest that schistosomiasis alters endothelial cell P2Y2R/P2X7R signaling during inflammation. These discoveries advance our understanding of schistosomiasis. This intricate interplay, driven by PAMP-triggered endothelial P2Y2R/P2X7R cross-talk, emerges as a potential key player in the mesenteric inflammation during schistosomiasis. [ABSTRACT FROM AUTHOR]

Quinolinic acid (QUIN) is a toxic compound with pro-oxidant, pro-inflammatory, and pro-apoptotic actions found at high levels in the central nervous system (CNS) in several pathological conditions. Due to the toxicity of QUIN, it is important to evaluate strategies to protect against the damage caused by this metabolite in the brain. In this context, coenzyme Q10 (CoQ10) is a provitamin present in the mitochondria with a protective role in cells through several mechanisms of action. Based on these, the present study was aimed at evaluating the possible neuroprotective role of CoQ10 against damage caused by QUIN in the striatum of young Wistar rats. Twenty-one-day-old rats underwent a 10-day pretreatment with CoQ10 or saline (control) intraperitoneal injections and on the 30th day of life received QUIN intrastriatal or saline (control) administration. The animals were submitted to behavior tests or euthanized, and the striatum was dissected to neurochemical studies. Results showed that CoQ10 was able to prevent behavioral changes (the open field, object recognition, and pole test tasks) and neurochemical parameters (alteration in the gene expression of IL-1β, IL-6, SOD, and GPx, as well as in the immunocontent of cytoplasmic Nrf2 and nuclear p-Nf-κβ) caused by QUIN. These findings demonstrate the promising therapeutic effects of CoQ10 against QUIN toxicity. [ABSTRACT FROM AUTHOR]