Induction Of Inflammatory Response Research Articles

Strain-specific differences in reovirus infection of murine macrophages segregate with polymorphisms in viral outer-capsid protein σ3.

Mammalian orthoreovirus (reovirus) strains type 1 Lang (T1L) and type 3 Dearing-RV (T3D-RV) infect the intestine in mice but differ in the induction of inflammatory responses. T1L infection is associated with the blockade of oral immunological tolerance to newly introduced dietary antigens, whereas T3D-RV is not. T1L infection leads to an increase in infiltrating phagocytes, including macrophages, in gut-associated lymphoid tissues that are not observed in T3D-RV infection. However, the function of macrophages in reovirus intestinal infection is unknown. Using cells sorted from infected intestinal tissue and primary cultures of bone-marrow-derived macrophages (BMDMs), we discovered that T1L infects macrophages more efficiently than T3D-RV. Analysis of T1L × T3D-RV reassortant viruses revealed that the viral S4 gene segment, which encodes outer-capsid protein σ3, is responsible for strain-specific differences in infection of BMDMs. Differences in the binding of T1L and T3D-RV to BMDMs also segregated with the σ3-encoding S4 gene. Paired immunoglobulin-like receptor B (PirB), which serves as a receptor for reovirus, is expressed on macrophages and engages σ3. We found that PirB-specific antibody blocks T1L binding to BMDMs and that T1L binding to PirB-/- BMDMs is significantly diminished. Collectively, our data suggest that reovirus T1L infection of macrophages is dependent on engagement of PirB by viral outer-capsid protein σ3. These findings raise the possibility that macrophages function in the innate immune response to reovirus infection that blocks immunological tolerance to new food antigens.IMPORTANCEMammalian orthoreovirus (reovirus) infects humans throughout their lifespan and has been linked to celiac disease (CeD). CeD is caused by a loss of oral immunological tolerance (LOT) to dietary gluten and leads to intestinal inflammation following gluten ingestion, which worsens with prolonged exposure and can cause malnutrition. There are limited treatment options for CeD. While there are genetic risk factors associated with the illness, triggers for disease onset are not completely understood. Enteric viruses, including reovirus, have been linked to CeD induction. We found that a reovirus strain associated with oral immunological tolerance blockade infects macrophages by virtue of its capacity to bind macrophage receptor PirB. These data contribute to an understanding of the innate immune response elicited by reovirus, which may shed light on how viruses trigger LOT and inform the development of CeD vaccines and therapeutic agents.

ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells

Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.

Arsenic trioxide induces innate immune response and inflammatory response in chicken liver via cGAS-STING/NF-κB pathway

Arsenic is a toxic metal-like element widely used in the pesticide, preservative and semiconductor industries. However, accumulation of arsenic through the food chain can cause serious damage to animal and human health. However, the toxic mechanism of arsenic-induced hepatotoxicity in chickens is not clear, and the present study aimed to investigate the potential role of cGAS-STING and NF-κB pathways on inflammatory injury in chicken liver. In this study, 75 white-feathered broilers were divided into a control group, a low-dose arsenic group (4 mg/kg) and a high-dose arsenic group (8 mg/kg) to investigate the toxic effects of arsenic on chicken liver. In this study, we found that pathological changes such as inflammatory cell infiltration and vesicular degeneration occurred in the liver when exposed to ATO. Crucially, exposure to ATO triggered the cGAS-STING pathway and markedly raised the levels of mRNA and protein expression of cGAS, STING, TBK1, and IRF7. The type I interferon response was also triggered. Simultaneously, STING induced the activation of the conventional NF-κB signaling pathway and stimulated the expression of genes associated with inflammation, such as IL-6, TNF-α and IL-1β. In summary, the induction of inflammatory responses via cGAS-STING and NF-κB signaling pathways under high ATO exposure provides new ideas for further studies on the toxicological mechanisms of arsenic.

Silybin attenuates avermectin-induced oxidative damage in carp respiration by modulating the cGAS-STING pathway and endoplasmic reticulum stress.

Avermectin is a commonly used insect repellent for aquaculture and crops, but it is easy to remain in the aquatic environment, causing organism disorders, inflammation, and even death. This resulted in significant economic losses to the carp aquaculture industry. Silybin has antioxidant, anti-inflammatory, and anti-apoptotic properties. However, it is unclear whether Silybin counteracts gill damage caused by avermectin exposure. Therefore, we modeled avermectin exposure and Silybin intervention by adding 2.404 μg/L avermectin to water and 400 mg/kg of Silybin to feed. Gill tissue was collected and analyzed in depth during a 30-day experimental period. The results showed that avermectin exposure induced structural disorganization of gill filaments and led to increased reactive oxygen species, inhibition of antioxidant functions, induction of inflammatory responses, and endoplasmic reticulum stress in addition to the endogenous apoptotic pathway. In contrast, Silybin effectively alleviated pathological changes and reduced reactive oxygen species levels, thereby attenuating oxidative stress and endogenous apoptosis and inhibiting endoplasmic reticulum stress pathways. In addition, Silybin reduced avermectin-induced gill tissue inflammation in carp, and it is considered that it might modulate the cGAS-STING pathway. In summary, Silybin alleviates avermectin-induced oxidative damage within the carp's respiratory system by modulating the cGAS-STING pathway and endoplasmic reticulum stress. The main goal is to understand how Silybin reduces oxidative damage caused by avermectin in carp gills, offering management strategies. Concurrently, the current study proposes that Silybin can serve as a dietary supplement to reduce the risks brought on by repellent buildup in freshwater aquaculture.

PRRSV infection facilitates the shedding of soluble CD163 to induce inflammatory responses

Porcine reproductive and respiratory syndrome (PRRS), which poses substantial threats to the global pig industry, is primarily characterized by interstitial pneumonia. Cluster of differentiation 163 (CD163) is the essential receptor for PRRSV infection. Metalloproteinase-mediated cleavage of CD163 leads to the shedding of soluble CD163 (sCD163), thereby inhibiting PRRSV proliferation. However, the exact cleavage site in CD163 and the potential role of sCD163 in inflammatory responses during PRRSV infection remain unclear. Herein, we found that PRRSV infection increased sCD163 levels, as demonstrated in primary alveolar macrophages (PAMs), immortalized PAM (IPAM) cell lines, and sera from PRRSV-infected piglets. With LC-MS/MS, Arg-1041/Ser-1042 was identified as the cleavage site in porcine CD163, and an IPAM cell line with precise mutation at the cleavage site was constructed. Using the precisely mutated IPAM cells, we found that exogenous addition of sCD163 protein promoted inflammatory responses, while mutation at the CD163 cleavage site suppressed inflammatory responses. Consistently, inhibition of sCD163 using its neutralizing antibodies reduced PRRSV infection-triggered inflammatory responses. Importantly, sCD163 promoted cell polarization from M2 to M1 phenotype, which in turn facilitated inflammatory responses. Taken together, our findings identify sCD163 as a novel proinflammatory mediator and provide valuable insights into the mechanisms underlying the induction of inflammatory responses by PRRSV infection.

P22 A single-cell map of the epigenomic landscape in keratinocytes exposed to the cytokine milieu of atopic dermatitis

Abstract Introduction and aims In atopic dermatitis (AD), induction of inflammatory responses regulated by cytokines such as of thymic stromal lymphopoietin exacerbate the disrupted integrity of the skin barrier. Cytokines, such as interleukin (IL)-4, IL-13 and IL-22, present in the skin milieu, bind to their corresponding receptors on the cell surface of keratinocytes, activating multiple signal transduction pathways that lead to changes in the gene expression profile of keratinocytes, in part, by modulating chromatin structure. Understanding the intricate interplay between cytokine-mediated signalling pathways in keratinocytes and the resulting epigenetic changes is essential for elucidating the pathogenesis of AD. In this study, we utilized high-throughput technology to examine the effects of cytokines on modulation of the epigenetic landscape at the keratinocyte single-cell level, and subsequent effects on the gene expression. Methods We utilized the reconstructed human epidermis model, an in vitro three-dimensional human epidermis model consisting of a polycarbonate membrane and keratinocytes mimicking the structure of native human epidermis. Following exposure to AD cytokine(s), the model gene expression and chromatin accessibility of target cells were analysed using single-cell multiomics approaches. Results Our preliminary data show that IL-4, IL-13 and IL-22 reduce the expression levels of the barrier-related gene filaggrin in keratinocytes. Conclusions Unlike genetic changes, epigenetic alterations are dynamic and can be restored to their normal state, which has major implications for the development of therapeutics for various diseases. This study will provide valuable insights into the epigenetic mechanisms underlying AD and present potential targets for epigenetic-related therapeutic interventions. These interventions can be used in combination with available compounds to reduce the recurrence of AD and improve the treatment efficiency.

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson's Disease and Aging.

Parkinson's disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors.

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

In vitro regulation of gene expression of pregnancy-associated proteins and cytokines in bovine endometrial epithelial cells and bovine trophoblastic cells by infection with Neospora caninum

Abortion caused by the parasite Neospora caninum is an important threat to the livestock industry worldwide. Trophoblasts and caruncular cells play major roles in initiating innate immune responses and controlling parasite infection at the fetal-maternal interface. In the present study, bovine uterine epithelial cells (BUECs) and bovine trophoblastic (BT) cells treated with bovine interferon-gamma (IFN-γ), IFN-alpha (IFN-α) and IFN-tau (IFN-τ) followed by infection with N. caninum were examined by measuring the mRNA expression levels of numerous pregnancy-associated proteins and observing parasite growth to elucidate the host-parasite interaction at the uteroplacental region. N. caninum infection increased the expression of prolactin-related protein 1 (PRP1), pregnancy-associated glycoprotein 1 (PAG1), and cytokines (TNF-α, IL-8 and IL-10) in BUECs and of IL-8 in BT cells. Bovine IFN-γ inhibited IL-8 and TNF-α expression in BUECs and IL-8 in BT cells. In contrast, the expression of the interferon-stimulated gene OAS1 was significantly increased by treatment of the infected BT cells with IFN-γ. However, treatment with bovine IFNs did not inhibit N. caninum growth in either cell line. In conclusion, our results suggest that bovine IFN-γ plays a crucial role in control of pathogenesis in uterus and induction of inflammatory response in the placental region following N. caninum infection, rather than growth inhibition of the parasites.

Porcine reproductive and respiratory syndrome virus infection activates ADAM17 to induce inflammatory responses

Porcine reproductive and respiratory syndrome (PRRS), which has posed substantial threats to the swine industry worldwide, is primarily characterized by interstitial pneumonia. A disintegrin and metalloproteinase 17 (ADAM17) is a multifunctional sheddase involved in various inflammatory diseases. Herein, our study showed that PRRS virus (PRRSV) infection elevated ADAM17 activity, as demonstrated in primary porcine alveolar macrophages (PAMs), an immortalized PAM cell line (IPAM cells), and the lung tissues of PRRSV-infected piglets. We found that PRRSV infection promoted ADAM17 translocation from the endoplasmic reticulum to the Golgi by enhancing its interaction with inactive rhomboid protein 2 (iRhom2), a newly identified ADAM17 regulator, which in turn elevated ADAM17 activity. By screening for PRRSV-encoded structural proteins, viral envelope (E) and nucleocapsid (N) proteins were identified as the predominant ADAM17 activators. E and N proteins bind with both ADAM17 and iRhom2 to form ternary protein complexes, ultimately strengthening their interactions. Additionally, we demonstrated, using an ADAM17-knockout cell line, that ADAM17 augmented the shedding of soluble TNF-α, a pivotal inflammatory mediator. We also discovered that ADAM17-mediated cleavage of porcine TNF-α occurred between Arg-78 and Ser-79. By constructing a precision mutant cell line with Arg-78-Glu/Ser-79-Glu substitution mutations in TNF-α, we further revealed that the ADAM17-mediated production of soluble TNF-α contributed to the induction of inflammatory responses by PRRSV and its E and N proteins. Taken together, our results elucidate the mechanism by which PRRSV infection activates the iRhom2/ADAM17/TNF-α axis to enhance inflammatory responses, providing valuable insights into the elucidation of PRRSV pathogenesis.

Abstract 5153: Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics

Abstract Background: Colorectal cancer (CRC) exhibits a heightened presence of intratumoral bacteria, and deficient DNA mismatch repair (dMMR) contributes to nucleotide mismatch accumulation, fostering mutagenesis. However, the combined impact of intratumoral bacteria and dMMR on the tumor immune microenvironment (TIME) in CRC, and its consequential influence on patient prognosis, remains elusive. Methods: We utilized samples from the Cancer Microbiome Atlas project (TCMA), collecting tumor and matched paracancer tissues from colorectal cancer patients. Phyloseq in R was employed to scrutinize microbial abundance differences. The effects of microbial enrichment on prognosis were assessed through survival analysis, and GSEA enrichment analysis provided mechanistic insights. Results: A total of 173 samples, including 28 dMMR tumors, 112 proficient MMR (pMMR) tumors, and 22 paired para-cancer tissues, were collected. Following stringent filtration, we analyzed 230 bacterial genera. Notably, 26 genera, including Fusobacterium and Streptococcus, showed significant enrichment in dMMR tumors compared to para-cancer tissues. Furthermore, 18 genera were enriched in dMMR tumors compared to pMMR tumors. Of these, 8 genera like Desulfovibrio and Pyramidobacter consistently exhibited enrichment in dMMR CRC compared to either para-cancer tissues or pMMR tumors. Survival analysis highlighted Pyramidobacter as the only genus significantly associated with prognosis in dMMR CRC. Increased Pyramidobacter abundance correlated with decreased overall survival (OS) (P value: 0.049). Stratifying dMMR CRC patients based on Pyramidobacter abundance further emphasized the significantly worse survival in the Pyramidobacter-High group (HR 0.93, 95%CI 1.03-9.60, log-rank p = 0.015). Exploring the impact of Pyramidobacter infection on tumor progression, we assessed TIME and oncogenic pathways between Pyramidobacter-Low and Pyramidobacter-High groups. While overall immune infiltration was higher in the Pyramidobacter-High group, it primarily stemmed from increased B cell and naive CD8+ T cell infiltration. Importantly, pathways enriched in the Pyramidobacter-High group included inflammatory response, epithelial-mesenchymal transition (EMT), and KRAS signaling, while those enriched in the Pyramidobacter-Low group encompassed IFNα response, IFNγ response, and DNA damage repair. These findings suggest Pyramidobacter's role in inducing inflammation, promoting tumor proliferation and metastasis, and suppressing interferon response. Conclusion: Pyramidobacter emerges as a key player in the development of dMMR CRC, exerting a pivotal influence on patient prognosis through the induction of inflammatory responses and EMT. Citation Format: Shisen LI, Yunlong LI, Hongjiang Ma, Shihao Qin, Feilong Zhao, Jipeng Li. Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5153.

Abstract 2964: Glutathione S-transferase omega 2 (GSTO2) suppresses the acquisition of the senescent tumor cells phenotype in lung adenocarcinoma

Abstract Cellular senescence is a phenomenon characterized by the cell cycle arrest and the induction of inflammatory responses, and is known to contribute to the development and progression of various diseases. In cancerous tissues, some cancer cells acquire the senescent traits, which are referred to as senescent tumor cells (STCs) and contribute to tumor invasion and metastasis. We have previously demonstrated that the expression of glutathione S-transferase omega 2 (GSTO2), which regulates the glutathione redox balance, is exclusively expressed in cells with regenerative ability such as airway basal cells, Clara cells, and type II alveolar cells in the lungs. Contrastingly, the expression of GSTO2 was completely lost in squamous cell carcinoma of the lung (Cancer Science, 2022); however, we found that some of lung adenocarcinoma expressed GSTO2. In this study, we aimed to clarify the significance of GSTO2 in lung adenocarcinoma, especially in the regulation of senescence and STCs. To examine whether GSTO2 expression affects senescence marker expression, we prepared GSTO2-transfected and mock-transfected lung adenocarcinoma cell line PC-9. Forced GSTO2 expression resulted in significantly reduced expression of senescence markers, such as p21, p53, and p16. We performed double staining for GSTO2 with p16 and confirmed the inverse correlation between them in lung adenocarcinoma tissues, where GSTO2-positive cells tended to express lower p16 level compared with GSTO2-negative cells. Furthermore, GSTO2-transfected PC-9 cells showed lower expression of senescence-associated secretory phenotype factors, such as IL-6, TNFα, and IL-1β than mock-transfected cells. These results suggest that GSTO2 suppresses senescence in lung adenocarcinoma cells. We next examined whether GSTO2 expression affects tumor cell growth because senescence is involved in the cell cycle arrest. Expectedly, MTT assay revealed that GSTO2 overexpression in PC-9 cells significantly promoted cell growth compared with the mock transfected cells. Contrastingly, the scratching assay showed that the cell migration of GSTO2-transfected PC-9 cells was significantly delayed compared with that of the mock-transfected cells. In conclusion, we demonstrated that GSTO2 regulates senescence, resulting in the suppression of cell migration. The expression of GSTO2 in lung adenocarcinoma may contribute to the inhibition of the emergence of STCs, being a cause of invasion and resistance to radiotherapy and chemotherapy. Citation Format: Hiroto Hatano, Ryusuke Sumiya, Teruki Hagiwara, Hiromu Suzuki, Kazuhiko Yamada, Norihiro Kokudo, Yuki Kawamura. Glutathione S-transferase omega 2 (GSTO2) suppresses the acquisition of the senescent tumor cells phenotype in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2964.

Abstract 176: Stearic acid induces pro-inflammatory macrophage response important for lung cancer development

Abstract Background Survival is improved with early detection and treatment initiation in patients with lung cancer (LC) emphasizing the importance of tumor initiation and biomarker development in individuals at high risk for developing LC and those with early-stage LC. Recent studies suggest that immunologic and metabolic changes within the microenvironment are pivotal for tumor formation. We recently demonstrated that in patients with resectable, early-stage LC, elevated levels of stearic acid (SA), a long chain fatty acid, and macrophage inflammatory protein 1β (MIP-1β/CCL4) were predictive of tumor affected lung lobes. Therefore, we hypothesize that SA promotes LC initiation through the activation of macrophages (MΦ) and production of proinflammatory cytokines like CCL4. Methods and Results: We performed untargeted metabolomics utilizing LC-MS from the plasma of patients with various stages of LC and found elevated levels of SA in patients with early-stage LC. To further study the mechanistic role of SA in tumorigenesis, cell lines including immortalized lung epithelial, LC cells, and immune (MΦ and T) cells were treated with SA. We found that physiological concentrations of SA did not affect cellular viability. However, in MΦ, SA induced expression of inflammatory (IL6, iNOS), and immunomodulatory (Arg1, CD206) genes suggesting a role for SA in promoting a pro-tumorigenic immunologic state. Additionally, analysis of the secretome from SA stimulated MΦ using single cell proteomic analysis (Isolight, Bruker Cellular Analysis, Inc), indicated a significant enrichment of polyfunctional MΦs with enhanced secretion of enriched effector and stimulatory cytokines. Furthermore, conditioned media derived from SA stimulated MΦ led to increased proliferation, as well as anchorage independent growth, of BEAS2B immortalized lung epithelial cells. Conclusion: Our data demonstrates plasma levels of SA are increased in early-stage compared to late-stage patients with LC. This observation corresponds to our prior data demonstrating enrichment of SA in the tumor affected lobes of patients with early-stage LC. Recent studies demonstrating the induction of inflammatory responses through MΦ activation in obese patients by circulating SA in blood corroborates our observations as well. Our data suggests that the SA effect on MΦ, is critical in LC initiation not only increasing proliferation but also induction of neoplastic transformation of immortalized lung epithelial cells. Furthermore, our data indicates that blood plasma levels of SA, a fatty acid understudied in tumor biology, could also be exploited as a potential biomarker for LC development in individuals at high-risk for LC development as well as those patients with early-stage disease. Citation Format: Amrita Roy, Martin Davis, Samuel Weinberg, Apurva Mallisetty, Alicia Hulbert, Frank D. Weinberg. Stearic acid induces pro-inflammatory macrophage response important for lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 176.

AgNPs-induced oxidative stress and inflammation confer an increased susceptibility to aquatic reovirus infection

Silver nanoparticles (AgNPs) are increasingly utilized in diverse fields due to their superior physical properties and antimicrobial effects. However, the continuous release of AgNPs into aquatic environments may pose potential hazards to aquatic animals and cause toxicological effects. Nevertheless, there is a lack of research regarding whether chronic exposure to AgNPs induces immunotoxicity that affects the susceptibility of aquatic animals to pathogens, and its precise mechanism of action remains largely unknown. Herein, by deploying AgNP stress and an aquatic reovirus (grass carp reovirus, GCRV) infection as a model system, we illustrated that exposure to AgNPs resulted in chronic oxidative stress and inflammatory effects in grass carp, which included the deposition of silver particles in tissues, impaired activity of antioxidant enzymes, overt tissue damage, imbalances of gut microbiota composition, and induction of inflammatory responses. Additionally, AgNPs exposure in conjunction with GCRV infection led to a noteworthy rise in viral loads and upregulation of pro-inflammatory genes, as compared to the control group. This work suggests that chronic stress by AgNPs may enhance susceptibility to aquatic virus infection through oxidative stress and inflammatory effects, providing fresh insights to elucidate the disease development in aquatic animals caused by heavy metal pollution.

Microglial Inflammatory Mechanisms in Stroke: The Jury Is Still Out

Microglia represent the main immune cell population in the CNS with unique homeostatic roles and contribution to broad neurological conditions. Stroke is associated with marked changes in microglial phenotypes and induction of inflammatory responses, which emerge as key modulators of brain injury, neurological outcome and regeneration. However, due to the limited availability of functional studies with selective targeting of microglia and microglia-related inflammatory pathways in stroke, the vast majority of observations remain correlative and controversial. Because extensive review articles discussing the role of inflammatory mechanisms in different forms of acute brain injury are available, here we focus on some specific pathways that appear to be important for stroke pathophysiology with assumed contribution by microglia. While the growing toolkit for microglia manipulation increasingly allows targeting inflammatory pathways in a cell-specific manner, reconsideration of some effects devoted to microglia may also be required. This may particularly concern the interpretation of inflammatory mechanisms that emerge in response to stroke as a form of sterile injury and change markedly in chronic inflammation and common stroke comorbidities.

Construction of the flagellin F mutant of Vibrio parahaemolyticus and its toxic effects on silver pomfret (Pampus argenteus) cells

Vibrio parahaemolyticus causes diseases in aquatic organisms, leading to substantial financial losses to the aquaculture industry; its flagellin F (flaF) protein triggers severe inflammation in host cells. To enhance the understanding of the function of flaF in V. parahaemolyticus infection, in this study, a flaF-deficient mutant was constructed by employing two-step homologous recombination. The flaF-deficient mutant induced a significantly lower toll-like receptor 5 (TLR5) expression and apoptosis in fish intestinal epithelial cells than the wild-type V. parahaemolyticus. Furthermore, fluorescence labelling and microscopy analysis of TLR5 showed that V. parahaemolyticus and its mutant strain significantly enhanced TLR5 expression. Additionally, the findings suggest that flaF deletion did not significantly affect the expression of myeloid differentiation factor 88 (MyD88) and interleukin-8 (IL-8) induced by V.parahaemolyticus. In summary, V. parahaemolyticus induced a TLR5-dependent inflammatory response and apoptosis through MyD88, which was observed to be influenced by flaF deletion. In this study, we obtained stable mutants of V. parahaemolyticus via target gene deletion—which is a rapid and effective approach—and compared the induction of inflammatory response and apoptosis by V. parahaemolyticus and its mutant strain, providing novel perspectives for functional gene research in V. parahaemolyticus.

Toll-like receptors and Streptococcus mutans: An updated review article.

It has been reported that toll-like receptors (TLRs) are the main innate immune receptors that recognize gram-positive pathogen-associated molecular patterns (PAMPs). The molecules can induce expression of the innate immune-related molecules that are essential against the bacteria. Streptococcus mutans (S. mutans) is a potential caries-associated pathogen, and innate immunity plays a key role in inhibiting its development and the progression of inflammatory responses. Recently, the roles played by TLRs against S. mutans and the induction of inflammatory responses were evaluated by several investigations. This review article discusses updated information regarding the roles played by TLRs and their potential therapeutic effects against S. mutans.

Inflammatory response induction as a result of BioGlue adhesive application in cardiac surgery - a review of the literature.

BioGlue is one of the best-known substances used as a tissue adhesive during surgical procedures, especially in cardiac surgery. Inappropriate use of BioGlue can result in inflammation in both the heart and adjacent tissues after its intraoperative application. Inflammation caused by BioGlue in cardiac surgery is a topic that has been discussed by numerous authors in scientific studies, meta-analyses and evaluations of this tissue adhesive. However, there is a lack of collected knowledge on this subject in a single concise article. The purpose of this paper is to review the current medical knowledge on the use of BioGlue in cardiac surgery versus the induction of an inflammatory response. Our paper discusses the details of this problem according to the most recent scientific reports.

Chapter 4 - Viral vectors for gene delivery to the central nervous system

Brain diseases with a known or suspected genetic basis represent an important frontier for advanced therapeutics. The central nervous system (CNS) is an intricate network in which diverse cell types with multiple functions communicate via complex signaling pathways, making therapeutic intervention in brain-related diseases challenging. Nevertheless, as more information on the molecular genetics of brain-related diseases becomes available, genetic intervention using gene therapeutic strategies should become more feasible. There remain, however, several significant hurdles to overcome that relate to (i) the development of appropriate gene vectors and (ii) methods to achieve local or broad vector delivery. Clearly, gene delivery tools must be engineered for distribution to the correct cell type in a specific brain region and to accomplish therapeutic transgene expression at an appropriate level and duration. They also must avoid all toxicity, including the induction of inflammatory responses. Over the last 40 years, various types of viral vectors have been developed as tools to introduce therapeutic genes into the brain, primarily targeting neurons. This review describes the most prominent vector systems currently approaching clinical application for CNS disorders and highlights both remaining challenges as well as improvements in vector designs that achieve greater safety, defined tropism, and therapeutic gene expression.

Pathological and virological findings of type I interferon receptor knockout mice upon experimental infection with Heartland virus

Heartland virus (HRTV) causes generalized symptoms, severe shock, and multiple organ failure. We previously reported that interferon-α/β receptor knockout (IFNAR-/-) mice infected intraperitoneally with 1 × 107 tissue culture-infective dose (TCID50) of HRTV died, while those subcutaneously infected with the same dose of HRTV did not. The pathophysiology of IFNAR-/- mice infected with HRTV and the mechanism underlying the difference in disease severity, which depends on HRTV infection route, were analyzed in this study. The liver, spleen, mesenteric and axillary lymph nodes, and gastrointestinal tract of intraperitoneally (I.P.) infected mice had pathological changes; however, subcutaneously (S.C.) infected mice only had pathological changes in the axillary lymph node and gastrointestinal tract. HRTV RNA levels in the mesenteric lymph node, lung, liver, spleen, kidney, stomach, intestine, and blood were significantly higher in I.P. infected mice than those in S.C. infected mice. Chemokine ligand-1 (CXCL-1), tumor necrosis factor (TNF)-α, interleukin (IL)-12, interferon (IFN)-γ, and IL-10 levels in plasma of I.P. infected mice were higher than those of S.C. infected mice. These results indicated that high levels of viral RNA and the induction of inflammatory responses in HRTV-infected IFNAR-/- mice may be associated with disease severity.