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Innate lymphoid cells (ILCs) are the main resident lymphocytes that mostly reside in tissues owing to the lack of adaptive antigen receptors. These cells are involved in early anti-infective immunity, antitumour immunity, regulation of tissue inflammation, and maintenance of homeostasis in the internal environment of tissues and have been referred to as the "first armies stationed in the human body". ILCs are widely distributed in the lungs, colon, lymph nodes, oral mucosa and even embryonic tissues. Due to the advantage of their distribution location, they are often among the first cells to come into contact with pathogens.Relevant studies have demonstrated that ILCs play an early role in the defence against a variety of pathogenic microorganisms, including bacteria, viruses, fungi and helminths, before they intervene in the adaptive immune system. ILCs can initiate a rapid, nonspecific response against pathogens prior to the initiation of an adaptive immune response and can generate a protective immune response against specific pathogens, secreting different effectors to play a role.There is growing evidence that ILCs play an important role in host control of infectious diseases. In this paper, we summarize and discuss the current known infectious diseases in which ILCs are involved and ILC contribution to the defence against infectious diseases. Further insights into the mechanisms of ILCs action in different infectious diseases will be useful in facilitating the development of therapeutic strategies for early control of infections. [ABSTRACT FROM AUTHOR]

Since the first description of dendritic cells by Steinman and Cohn in 1973, this important cell type has gained increasing attention. Over 4000 papers have been published on this topic annually during the last few years. At the beginning, dendritic cells were recognized for their immune stimulatory properties and their importance in initiating an adaptive immune response. Later, it was found that dendritic cells do not only initiate but also regulate immune responses. This attribute makes the so-called regulatory dendritic cells highly important for the prevention of exaggerated immune responses. Immune cells make contact with different Ags every day and must be tightly controlled to prevent excessive inflammation and subsequent organ destruction, particularly in organs such as the gut and lungs. Here, we give a brief overview of our current knowledge on how immune responses are controlled by dendritic cells, highlighting how they are involved in the induction of peripheral tolerance. We focus on what is known about these processes in the lung, with a closer look at their role in the induction and control of diseases such as bronchial asthma, chronic obstructive pulmonary disease and lung infections. Finally, we summarize some current approaches to modulate the behavior of dendritic cells that may hopefully lead to future therapeutics to control exaggerated immune responses. [ABSTRACT FROM AUTHOR]

A meta-analysis was carried out in this study by summarizing relevant research to evaluate the relationship between rs2107538 polymorphism in the chemotactic chemokine ligand 5 (CCL5) gene and tuberculosis (TB) susceptibility. Published studies were retrieved from PubMed, Embase, and CNKI databases using the keywords 'CCL5', 'TB', and 'polymorphism'. Nine studies involving 2584 patients with TB and 2265 controls were included in the current meta-analysis. The combined results suggested that the CCL5 rs2107538 polymorphism was correlated with TB susceptibility (recessive model: OR = 1.45, 95% CI = 1.02–2.07). Subgroup analysis according to race indicated that such correlation could be detected in Caucasians (CT versus CC: OR = 1.53, 95% CI = 1.20–1.95; dominant model: OR = 1.58, 95% CI = 1.25–1.99), but not in East Asian, South Asian, and South African populations. In conclusion, the results of our meta-analysis suggest that CCL5 rs2107538 polymorphism might contribute to the risk of TB, especially in Caucasians. Well-designed studies with more subjects will be required for further validation of these results. [ABSTRACT FROM AUTHOR]

Th2 polarization is essential for the pathogenesis of allergic rhinitis (AR). Th2 polarization's mechanism requires further understanding. IL-4 is the primary cytokine involved in Th2 response. Fibroblasts play a role in immune regulation. This study aims to elucidate the role of nasal mucosal fibroblast-derived IL-4 in the induction of Th2 responses. Nasal mucosal tissues were obtained from surgically removed samples from patients with nasal polyps, whether with or without AR. Fibroblasts were isolated from the tissues by flow cytometry cell sorting, and analyzed by RNA sequencing (RNAseq). The data from RNAseq showed that nasal fibroblasts expressed genes of GATA3, CD80, CD83, CD86, STAT6, IL2, IL4, IL5, IL6, IL13 and costimulatory factor. The data were verified by RT-qPCR. The level of gene activity was positively correlated with those of AR-related cytokines present in nasal secretions. Nasal fibroblasts release IL-4 upon activation. Nasal fibroblasts had the ability to transform naive CD4+ T cells into Th2 cells, which can be eliminated by inhibiting IL-4 receptor or CD28 in CD4+ T cells. To sum up, nasal mucosal fibroblasts produce IL-4, which can induce Th2 cell development. The data implicate that nasal fibroblasts are involved in the pathogenesis of nasal allergy. [ABSTRACT FROM AUTHOR]

Macrophages are present in many mechanically active tissues and are often subjected to varying degrees of mechanical stimulation. Macrophages play a crucial role in resisting pathogen invasion and maintaining tissue homeostasis. Piezo-type mechanosensitive channel component 1 (Piezo1) is the main cation channel involved in the rapid response to mechanical stimuli in mammals. This channel plays a crucial role in controlling blood pressure and motor performance and regulates urinary osmotic pressure and epithelial cell proliferation and division. In recent years, numerous studies have shown that in macrophages, Piezo1 not only plays a role in regulating the aforementioned physiological processes but also participates in multiple pathological processes such as inflammation and cancer. In this review, we summarize the research progress on Piezo1-mediated regulation of macrophage-mediated inflammatory responses through downstream signalling pathways and the aerobic glycolysis pathway. [ABSTRACT FROM AUTHOR]

Lipopolysaccharides (LPSs) from Gram-negative bacteria are strong elicitors of the human immune systems. There is strong evidence that aggregates and not monomers of LPS play a decisive role at least in the initial stages of cell activation of immune cells such as mononuclear cells. In previous reports, it was shown that the biologically most active part of enterobacterial LPS, hexa-acyl bisphosphorylated lipid A, adopts a particular supramolecular conformation, a cubic aggregate structure. However, little is known about the size and morphology of these aggregates, regarding the fact that LPS may have strong variations in the length of the saccharide chains (various rough mutant and smooth-form LPS). Thus, in the present paper, several techniques for the determination of details of the aggregate morphology such as freeze-fracture and cryo-electron microscopy, analytical ultracentrifugation, laser backscattering analysis, and small-angle X-ray scattering were applied for various endotoxin (lipid A and different LPS) preparations. The data show a variety of different morphologies not only for different endotoxins but also when comparing different applied techniques. The data are interpreted with respect to the suitability of the single techniques, in particular on the basis of available literature data. [ABSTRACT FROM PUBLISHER]

The importance of accessory signaling pathways amplifying endotoxin responses has recently been highlighted by genetic studies describing LPS-hyporesponsive individuals despite carrying the common allele for TLR4. The nucleotide receptor P2X7 modulates the production of numerous LPS-stimulated inflammatory mediators. We have recently described the largest phenotypic screen known for genetic polymorphisms associated with the nucleotide receptor P2X7, a global regulator of leukocyte function. This required the development of a novel monocyte pore assay with numerous advantages over previous methods and with the potential to facilitate rapid (< 3 h), multiplex analysis of clinical samples. This paper addresses aspects pertinent to the development of the monocyte pore assay, briefly summarizes our results suggestingthat P2X7 alleles modulate LPSstimulated cytokine production, and discusses a model wherein P2X7 may serve as an amplification loop of innate immunity. [ABSTRACT FROM PUBLISHER]

Acute lung injury (ALI) is the leading cause of death in patients with sepsis syndrome and without effective protective or therapeutic treatments. Acacetin, a natural dietary flavonoid, reportedly exerts several biological effects, such as anti-tumor, anti-inflammatory, and anti-oxidative effects. However, acacetin's effect and underlying mechanism on sepsis-induced ALI remain unclear. Here, the mouse model was established to explore the impact of acacetin on sepsis-induced ALI. Acacetin significantly increased ALI murine survival and attenuated lung injury in histological examinations. Additionally, acacetin down-regulated myeloperoxidase activity, protein concentration, and number of neutrophils and macrophages in bronchoalveolar lavage fluid. Subsequently, inflammatory cytokines, including TNF-α, IL-1β, and IL-6, were examined. Results showed that acacetin dramatically suppressed the production of TNF-α, IL-1β, and IL-6. These above results indicated that acacetin attenuated sepsis-induced ALI by inhibiting the inflammatory response. Moreover, acacetin inhibited the expression of markers for M1-type (iNOS, CD86) macrophages and promoted the expression of markers for M2-type (CD206, Arg1) macrophages by western blot. In addition, acacetin down-regulated the expression TRAF6, NF-κB, and Cyclooxygenase-2 (COX2) by western blot. The high concentration of acacetin had a better effect than the low concentration. Besides, over-expression of TRAF6 up-regulated the expression of COX2, CD86, and iNOS, and the ratio of p-NF-κB to NF-κB increased the mRNA levels of TNF-α, IL-1β, and IL-6, down-regulated the expression of CD206 and Arg1. The effects of TRAF6 were the opposite of acacetin. And TRAF6 could offset the impact of acacetin. This study demonstrated that acacetin could prevent sepsis-induced ALI by facilitating M2 macrophage polarization via TRAF6/NF-κB/COX2 axis. [ABSTRACT FROM AUTHOR]

Mammalian systems respond to environmental stress by either adapting for survival or undergoing programmed cell death (apoptosis). While it is generally believed that the caspase family of proteases are essential effectors of the apoptotic response, much less is clear about the signaling machinery required to activate the caspase system in response to stress stimuli. In the past few years, increasing evidence has linked the sphingomyelin and c-jun kinase (JNK) pathways to the death response in various cellular systems. Both signaling pathways are evolutionarily conserved through yeast. Since yeast does not undergo apoptosis, these pathways appear evolutionarily older than the caspase-mediated death programs. This paper reviews the role of sphingomyelin/ceramide and the JNK pathways in co-ordinating the signaling events leading to apoptosis. [ABSTRACT FROM PUBLISHER]

Endotoxin is thought to play a major role in septic shock and multiple systemic organ failure (MOF). However, endotoxin is not always detected in the plasma during Gram-negative sepsis by current Limulus lysate assays. Additionally, it is unknown to what extent the biological activity of endotoxin is truly reflected in endotoxemia. This paper assesses quantitatively a comparison of three types of Limulus assays for the detection of the biological activity of endotoxin in plasma. Mouse lethal activity and TNF production were used for assessment of the biological activity of endotoxin both before and after potential modification of LPS activity by plasma constituents. We have concluded that the dilution and heating method coupled with a toxinometer provides the most accurate correlation with other biological activities of endotoxin in plasma. The fact that the biological activity of endotoxin decreased to 17% of initial dose after incubation at 37ºC for 90 min in normal plasma suggests further a temporal dependence of time in plasma upon the manifestation of biological activities normally attributable to this biologically active microbial constituent found in the plasma of septic patients. [ABSTRACT FROM PUBLISHER]

Mucosal surfaces represent a natural colonization site for Gram-negative bacteria. We have already demonstrated the biologic role of Salmonella typhimurium porins in vitro and in vivo. In this paper we studied mucosal and systemic interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) production in systematically challenged mice or after intravesical administration of LPS or porins from S. typhimurium. It was found that serum IL-6 levels increased in BALB/c mice 4 h after receiving either i.v. LPS or porins from S. typhimurium. The porin challenge was stronger. Serum IL-6 levels were higher after porins than after LPS. IL-6 was not detected in the urine of i.v. challenged mice. Findings regarding IL-6 urine levels in intravesically treated mice were comparable. In porin-challenged mice they decreased more slowly than the LPS-challenged ones. IL-6 was not detected in the serum of intravesically challenged mice. In i.v. LPS-challenged mice, serum TNFα levels peaked earlier (at 2 h) than the IL-6 levels. A higher 2 h peak was instead seen in porin-challenged mice. TNFα was not detected in the urine of i.v. challenged mice. With intravesical LPS challenge, urinary TNFα levels peaked at 24 h, whereas in the porin-challenged mice the peak occurred 12 h earlier and was higher. Serum samples revealed no detectable TNFα. These findings confirm that both porins and LPS activate the mucosal response, without any systemic involvement, as, for example, in patients with diseases such as pyelonephritis or gastroenteritis. [ABSTRACT FROM PUBLISHER]

The development of effective pharmacotherapies to combat the Adult Respiratory Distress Syndrome (ARDS) is critically dependent upon: (1) the development of clinically-relevant animal models; (2) identification of inflammatory mediators centrally involved in eliciting lung injury; (3) understanding the inter-relationships or 'cross-talk' between pro and anti-inflammatory mediators which modulate the lung inflammation; and (4) the application of molecular techniques to isolate potentially novel genes involved in the development of ARDS. In this paper, we will present evidence from a rat model of microvascular lung injury produced by interleukin-2 (IL-2), that pulmonary TNFα is a primary and pivotal mediator of lung injury and that different modes of TNFα inhibition may represent feasible strategies to prevent ARDS. Furthermore, we will describe how the application of Differential Display Reverse Transcriptase Polymerase Chain Reaction (DDRT-PCR) can allow the rapid isolation of partial fragments of potentially new genes involved in ARDS. The products of such genes could represent future target sites for pharmacotherapeutic intervention. [ABSTRACT FROM PUBLISHER]

The study of cellular immune responses in animal disease models demands detailed knowledge of development, function, and regulation of immune cells, including natural killer (NK) cells. Listeria monocytogenes (LM) bacterium has been explored in a large area of research fields, including the host pathogen interaction. Although the importance role of NK cells in controlling the first phase of LM burden has been investigated, the interaction between NK cells and infected cells in details are far from being comprehended. From in vivo and in vitro experiments, we can drive several important pieces of knowledge that hopefully contribute to illuminating the intercommunication between LM- infected cells and NK cells. Experimental studies performed in rats revealed that certain NK cell ligands are influenced in LM- infected cells. These ligands include both classical- and non-classical MHC class I molecules and C-type lectin related (Clr) molecules that are ligands for Ly49- and NKR-P1 receptors respectively. Interaction between these receptors:ligands during LM infection, demonstrated stimulation of rat NK cells. Hence, these studies provided additional knowledge to the mechanisms NK cells utilise to recognise and respond to LM infection outlined in the current review. [ABSTRACT FROM AUTHOR]

In 1955, he defended his PhD on hormones and infection and started working at the Institut Pasteur (Paris) in the laboratory of Therapeutic Chemistry under André Lamensans. Graph Louis Selim Chedid was born in Cairo (Egypt) in June 1922 and died in Paris in March 2021 at the age of 98. 10 Leclerc C, Bahr GM, Chedid L. Marked enhancement of macrophage activation induced by synthetic muramyl dipeptide (MDP) conjugate using monoclonal anti-MDP antibodies. [Extracted from the article]

It is now well recognized that plasma LPS-binding protein (LBP) and membrane CD14 present at the surface of cells of the myelo/monocytic lineage are central molecules of the innate immune system, in response to LPS or to bacterial products. This paper reviews the role of LBP and CD14 in models of endotoxemia and infection. [ABSTRACT FROM PUBLISHER]

Pyrogens are classified in two groups, endotoxin pyrogens and non-endotoxin pyrogens (NEPs). The presence of either in parenteral pharmaceuticals or medical devices can cause severe harm to subjects, and when occurring in combination, synergistic potentiation effects can occur. As the standard in vitro pyrogen test, the Limulus Amebocyte Lysate (LAL) assay can detect LPS only, an endotoxin, but not NEPs. We tested whether the Monocyte Activation Test (MAT) that measures IL-6 induction, is suited for detecting synergistic pyrogen effects. Here we show that MAT reliably detects the NEPs heat-killed Staphylococcus aureus, R848 and lipoteichoic acid, in addition to LPS. When combinations of these pyrogens were tested, a potentiation of IL-6 production was seen beyond an additive effect, apparently reflecting on in-vivo synergisms. The current study therefore demonstrates that MAT not only is a reliable and reproducible assay for the sensitive detection of both endotoxin and non-endotoxin pyrogens, but also for identifying synergistic effects when parenteral drugs are contaminated with multiple pyrogens. [ABSTRACT FROM AUTHOR]

Species differences in the structure and function of the immune system of laboratory animals are known to exist and have been reviewed extensively. However, the number and diversity of wild and exotic species, along with their associated viruses, that come into contact with humans has increased worldwide sometimes with lethal consequences. Far less is known about the immunobiology of these exotic and wild species. Data suggest that species differences of the mechanisms of inflammation, innate immunity and adaptive immunity are all involved in the establishment and maintenance of viral infections across reservoir hosts. The current review attempts to collect relevant data concerning the basics of innate and adaptive immune functions of exotic and wild species followed by identification of those differences that may play a role in the maintenance of viral infections in reservoir hosts. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the role of hsa_circRNA_0000205 (circ_0000205) in chondrocyte injury in osteoarthritis (OA) and the underlying mechanism. Expression of circ_0000205, microRNA (miR)-766-3p and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5 was detected by quantitative real time (qRT)-polymerase chain reaction (PCR) and Western blot assays. Cell proliferation, apoptosis, and extracellular matrix (ECM) synthesis were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 5-ethynyl-2-deoxyuridine assays, flow cytometry, and qRT-PCR and Western blot assays. The target relationship between miR-766-3p and circ_0000205 or ADAMTS5 was confirmed by luciferase reporter assay and RNA immunoprecipitation. IL-1β treatment could attenuate cell viability of primary chondrocytes and proliferating cell nuclear antigen (PCNA) and collagen II type alpha-1 (COL2A1) levels, and elevate apoptosis rate and cleaved caspase-3, ADAMTS5 and matrix metalloproteinase-13 (MMP13) levels, suggesting that IL-1β induced chondrocyte apoptosis and ECM degradation. Expression of circ_0000205 was up-regulated in OA tissues and IL-1β-induced primary chondrocytes, accompanied with miR-766-3p down-regulation and ADAMTS5 up-regulation. Knockdown of circ_0000205 could mitigate IL-1β-induced above effects and improve cell proliferation. Moreover, both depleting miR-766-3p and promoting ADAMTS5 could partially counteract circ_0000205 knockdown roles in IL-1β-cultured primary chondrocytes. Notably, circ_0000205 was verified as a sponge for miR-766-3p via targeting, and ADAMTS5 was a direct target for miR-766-3p. Silencing circ_0000205 could protect chondrocytes from IL-1β-induced proliferation reduction, apoptosis, and ECM degradation by targeting miR-766-3p/ADAMTS5 axis. [ABSTRACT FROM AUTHOR]

Revisiting Metchnikoff's work in light of the COVID-19 pandemic illustrates how much this amazing scientist was a polymath, and one could speculate how much he would have been fascinated and most interested in following the course of the pandemic. Since he coined the word "gerontology", he would have been intrigued by the high mortality among the elderly, and by the concepts of immunosenescence and inflammaging that characterize the SARS-CoV-2 infection. While Metchnikoff's work is mainly associated with the discovery of the phagocytes and the birth of cellular innate immunity, he regularly invited his closest collaborators to investigate humoral immunity, and it was in his laboratory that Jules Bordet made his major discovery of the complement system. While Metchnikoff and his team investigated many infectious diseases, he also contributed to studies linked to vaccination, such as those on typhoid fever performed in chimpanzees, illustrating that non-human primates can provide animal models which are potentially helpful for understanding the pathophysiology of the COVID-19 virus. In the present review, we illustrate how much his own work and the investigations of his trainees were pertinent to this new disease. [ABSTRACT FROM AUTHOR]

Crohn's disease activates the inflammatory reactions to induce intestinal disorders. Enteral nutrition (EN) could exert general immunomodulatory effects. Cecal ligation and perforation (CLP) surgery was utilized to establish Crohn's disease mice models. Survival analysis, hematoxylin-eosin staining, flow cytometry, ELISA, Western blot and liquid chromatography-tandem MS were applied. Baicalein was added to inhibit lipoxygenases. The survival rate was restored and inflammatory injury, exudate neutrophils in peritoneal lavage and serum levels of IL-6 and TNF-α were ameliorated by EN treatment as compared with CLP treatment. EN also increased ILC-3 content, 5/15-LOX level and RvD1-RvD5 in peritoneal lavage. Baicalein reversed all the detected effects of EN except ILC-3 content. EN could activate special pro-resolving mediators (SPMs) through ILCs to mitigate injuries of Crohn's disease. [ABSTRACT FROM AUTHOR]

Innate immunomodulation via induction of innate memory is one mechanism to alter the host's innate immune response to reduce or prevent disease. Microbial products modulate innate responses with immediate and lasting effects. Innate memory is characterized by enhanced (training) or depressed (tolerance) innate immune responses, including pro-inflammatory cytokine production, to secondary exposure following a priming event. To investigate the ability of β-glucans and bacillus Calmette-Guerin to induce innate training or tolerance in pig cells, porcine monocytes were cultured with priming agonist (β-glucans or bacillus Calmette-Guerin) then re-stimulated 5 d later with a heterologous microbial agonist to determine induction of innate memory. Priming with β-glucan from Saccharomyces cerevisiae depressed IL-1β and TNF-α cytokine responses to re-stimulation with LPS, indicative of a tolerized state. However, bacillus Calmette-Guerin priming induced a trained state in porcine monocytes, as LPS re-stimulation enhanced IL-1β and TNF-α gene expression and protein production. We present the first evidence of innate memory in pig monocytes, with bacillus Calmette-Guerin (training) or Saccharomyces cerevisiae β-glucan (tolerance). Induction of a trained or tolerized state in vitro is a first step to identify agonists to alter the innate immune system at the animal level with the intent of enhancing disease resistance. [ABSTRACT FROM AUTHOR]

Non-typeable Haemophilus influenzae (NTHi) is the most common respiratory pathogen in patients with chronic obstructive disease. Limited data is available investigating the impact of NTHi infections on cellular re-differentiation processes in the bronchial mucosa. The aim of this study was to assess the effects of stimulation with NTHi on the bronchial epithelium regarding cellular re-differentiation processes using primary bronchial epithelial cells harvested from infection-free patients undergoing bronchoscopy. The cells were then cultivated using an air-liquid interface and stimulated with NTHi and TGF-β. Markers of epithelial and mesenchymal cells were analyzed using immunofluorescence, Western blot and qRT-PCR. Stimulation with both NTHi and TGF-ß led to a marked increase in the expression of the mesenchymal marker vimentin, while E-cadherin as an epithelial marker maintained a stable expression throughout the experiments. Furthermore, expression of collagen 4 and the matrix-metallopeptidases 2 and 9 were increased after stimulation, while the expression of tissue inhibitors of metallopeptidases was not affected by pathogen stimulation. In this study we show a direct pathogen-induced trans-differentiation of primary bronchial epithelial cells resulting in a co-localization of epithelial and mesenchymal markers and an up-regulation of extracellular matrix components. [ABSTRACT FROM AUTHOR]

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases. [ABSTRACT FROM AUTHOR]

Nuclear hormone receptor ligands are known to modulate innate immunity by dampening the immune response induced by pathogens. Here, we report that unlike other ligands, 3,3′,5-triiodo- l -thyronine (T3) induced the type 1 IFN response and expression of IFN-stimulated genes (ISGs). T3 action was found to be significantly amplified at supraphysiological concentrations (SPC) and in combination with double-stranded RNA mimic polyinosinic–polycytidylic acid. Induction by T3 was due to non-genomic mechanisms involving integrin binding, calcium mobilization, and phosphatidyl-inositol 3-kinase–AKT pathways, but was independent of TLR3, RIG-I, and IFN-β1 pathways. Whereas siRNA-induced knockdown of RNA-activated protein kinase (PKR) was found to abrogate the T3-induced expression of select ISGs, expression of other T3-induced ISGs was strongly induced by PKR knockdown, indicating the differential role of PKR in modulating T3 action. Together, we describe a novel role of T3 in modulating the innate immune response and identify the importance of PKR in regulating T3-induced immune activation. These findings have important implications in the basic understanding of the mechanisms of T3 function at SPCs and crosstalk involved in the thyroid hormone function and the innate immune response. [ABSTRACT FROM AUTHOR]

Although monocytes represent an essential part of the host defence system, their accumulation and prolonged stimulation could be detrimental and may aggravate chronic inflammatory diseases. The present study has explored the less-understood immunomodulatory effects of mesenchymal stem cells on monocyte functions. Isolated purified human monocytes were co-cultured with human umbilical cord-derived mesenchymal stem cells under appropriate culture conditions to assess monocytes' vital functions. Based on the surface marker analysis, mesenchymal stem cells halted monocyte differentiation into dendritic cells and macrophages and reduced their phagocytosis functions, which rendered an inability to stimulate T-cell proliferation. The present study confers that mesenchymal stem cells exerted potent immunosuppressive activity on monocyte functions such as differentiation, phagocytosis and Ag presentation; hence, they promise a potential therapeutic role in down-regulating the unwanted monocyte-mediated immune responses in the context of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Neutrophils are innate immune cells implicated in the process of killing Mycobacterium tuberculosis early during infection. Once the mycobacteria enter the human system, neutrophils sense and engulf them. By secreting bactericidal enzymes and α-defensins like human neutrophil peptides loaded in their granule armory, neutrophils kill the pathogen. Peripheral blood neutrophils secrete a wide range of cytokines like IL-8, IL-1-β and IFN-γ in response to mycobacterial infection. Thus they signal and activate distant immune cells thereby informing them of prevailing infection. The activated monocytes, dendritic cells and T cells further continue the immune response. As a final call, neutrophils release neutrophil extracellular traps in circulation which can trap mycobacteria in patients with active pulmonary tuberculosis. Extensive neutrophilic response is associated with inflammation, pulmonary destruction, and pathology. For example, inappropriate phagocytosis of mycobacteria-infected neutrophils can damage host cells due to necrosis of neutrophils, leading to chronic inflammation and tissue damage. This dual nature of neutrophils makes them double-edged swords during tuberculosis, and hence data available on neutrophil functions against mycobacterium are controversial and non-uniform. This article reviews the role of neutrophils in tuberculosis infection and highlights research gaps that need to be addressed. We focus on our understanding of new research ideologies targeting neutrophils (a) in the early stages of infection for boosting specific immune functions or (b) in the later stages of infection to prevent inflammatory conditions mediated by activated neutrophils. This would plausibly lead to the development of better tuberculosis vaccines and therapeutics in the future. [ABSTRACT FROM AUTHOR]

André Boivin (1895–1949) started his career in Marseille as a biochemist. Soon after the discovery of insulin, he worked on its purification, allowing for the treatment of local patients. He later moved to Strasbourg and set-up a microtitration technique of small carbon molecules and a method for quantifying purine and pyrimidine bases. His main scientific contribution occurred in Bucharest, where he was recruited to organize the teaching of medicinal chemistry. Together with Ion and Lydia Mesrobeanu, at the Cantacuzene Institute, they were the first to characterize the biochemical nature of endotoxins, which he termed the "glucido-lipidic antigen." After joining the Institut Pasteur annex near Paris, he worked with Gaston Ramon pursuing his research on smooth and rough LPS. Additionally, with Albert Delaunay, he researched the formation of exotoxins and antibodies (Abs). He was nominated assistant-director of the Institut Pasteur in 1940. He initiated research on bacterial DNA and RNA, and was the first to hypothesize on how RNA fits into gene function. In 1947 he moved for a second time to Strasbourg, accepting a position as a Professor of Biological Chemistry. After his premature death at the age of 54, the French academies mourned his loss and recognized him as one of their outstanding masters of biochemistry, microbiology, immunology, and molecular biology. [ABSTRACT FROM AUTHOR]

This study aimed to observe dynamically the changes of x-ray, histomorphology appearance and serum inflammatory cytokines of cervical degenerative disease in rat models and to discuss the mechanism of cervical degeneration. Sixty Sprague Dawley rats were randomised into test (n = 45) and control (n = 15) groups, which were randomly subdivided into three groups corresponding to 1, 3 and 6 mo post operation. At the corresponding postoperative stage, cervical x-ray films were acquired, and intervertebral disc space and intervertebral foramen size were measured. Some serum inflammatory cytokines from all rats were quantitatively determined. Then, the morphological change in cervical intervertebral disc specimens stained with hematoxylin and eosin was observed. The results were analysed and compared among groups. Compared to the control group, the cervical x-ray and histomorphology appearance of rats in the test group showed varying degrees of degeneration. Furthermore, the serum IL-1β, TNF-α and IL-10 in the test group increased significantly at the corresponding postoperative stage (P < 0.05, P < 0.01 and P < 0.001, respectively) compared to the control group. This model of cervical disc degeneration can accelerate imaging and histological degeneration, but it may be accompanied by changes in serum inflammatory cytokines levels. [ABSTRACT FROM AUTHOR]

Gut bacterial translocation following impaired gut barrier is a critical determinant of initiating and aggravating acute pancreatitis (AP). Antibiotic combination (ABX; vancomycin, neomycin and polymyxin b) is capable of reducing gut bacteria, but its efficacy in AP prevention and the underlying mechanism have not been investigated yet. AP was induced in BALB/c mice by caerulein (CAE) hyperstimulation. We found that ABX supplementation attenuated the severity of AP as evidenced by reduced pancreatic oedema and myeloperoxidase activity. The protective effect was also confirmed by improved histological morphology of the pancreas and decreased pro-inflammatory markers (IL-1β, TNF-α, MCP-1) in pancreas. ABX administration inhibits the activation of colonic TLR4/NLRP3 inflammasome pathway. Subsequently, down-regulated NLRP3 resulted in decreased colonic pro-inflammation (IL-1β, IL-6, MCP-1) and enhanced gut physical barrier as evidenced by up-regulation of tight junction proteins including occludin, claudin-1 and ZO-1, as well as improved histological morphology of the colon. Together, combinatory ABX therapy inhibited the translocation of gut bacteria to pancreas and its amplification effects on pancreatic inflammation by inhibiting the pancreatic NLRP3 pathway, and inhibiting intestinal-pancreatic inflammatory responses. The current study provides the basis for potential clinical application of ABX in AP. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine whether IL-6 polymorphisms correlate with sepsis. According to the inclusion criteria, the association of IL-6 polymorphisms with sepsis was searched in databases and analysed using comprehensive meta-analysis software. A total of 16 studies were included in this meta-analysis. There was no significant association between the IL-6-174G/C polymorphism and sepsis risk in the total population (C vs. G: OR = 1.04, 95% CI = 0.79–1.38; CC vs. GG: OR = 0.86, 95% CI = 0.53–1.41; CG vs. GG: OR = 0.99, 95% CI = 0.79–1.24; dominant model: OR = 0.97, 95% CI = 0.74–1.29; recessive model: OR = 0.92, 95% CI = 0.61–1.39). When patients were stratified according to ethnicity, a statistically significant association was observed in Asians and Africans. As for the -572G/C polymorphism, the results showed that the IL-6-572C/G polymorphism was not associated with sepsis susceptibility (G vs. C: OR = 0.98, 95% CI = 0.79–1.22; GG vs. CC: OR = 1.46, 95% CI = 0.53–4.03; GC vs. CC: OR = 0.82, 95% CI = 0.54–1.27; dominant model: OR = 0.88, 95% CI = 0.55–1.41; recessive model: OR = 1.55, 95% CI = 0.82–2.92). The data indicated that the IL-6-174G/C polymorphism may contribute to sepsis risk, especially in Africans and Asians. No significant association was observed between the IL-6-572G/C polymorphism and sepsis risk. [ABSTRACT FROM AUTHOR]

Many studies have demonstrated that (IL-18) polymorphisms (including -137C/G and -607A/C) are correlated with the risk of tuberculosis. However, the meaning of this finding remains a matter of debate. In this study, electronic databases, including PubMed, EMBASE, Web of Science, Google Scholar and CNKI, were systemically queried to identify relevant studies. Subsequently, odds ratios and corresponding 95% confidence intervals were analysed. Our data indicated that the IL-18 -137C/G polymorphism was not related to tuberculosis susceptibility (GG vs. AA odds ratio = 0.71, 95% confidence interval 0.43–1.17; GA vs. AA: odds ratio =0.80, 95% confidence interval 0.57–1.13; dominant model: odds ratio = 0.78, 95% confidence interval 0.56–1.08; recessive model: odds ratio = 0.76, 95% confidence interval 0.46–1.25). Similarly, there was no association between the IL-18 -607A/C polymorphism and tuberculosis susceptibility (AA vs. CC: odds ratio = 1.25, 95% confidence interval 0.87–1.79; CA vs. CC: odds ratio = 1.10, 95% confidence interval 0.93–1.29; dominant model: odds ratio = 1.13, 95% confidence interval 0.90–1.41; recessive model: odds ratios=1.17, 95% confidence interval 0.90–1.53). No association was found in the subgroup analysis based on the Hardy–Weinberg equilibrium. In addition, there was no publication bias. The two IL-18 gene polymorphisms (-137C/G and -607A/C) were not markedly correlated with tuberculosis susceptibility. Well-designed studies with more subjects will be required for further validation of these results. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that the immunological function of leukocytes is dependent on their cellular metabolism, and some researchers have advocated the beneficial effects of pioglitazone against sepsis in young mice, although bacterial infections are more prevalent in elderly hosts. Here, we investigated pioglitazone's preventative effect against sepsis induced by intravenous injection of a lethal dose of Escherichia coli in elderly mice (50–60 wk old) and examined its immunological and metabolic effects on liver leukocytes. Pioglitazone improved bacterial elimination in the peripheral blood, lowered serum pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ), and prevented septic death. It also enhanced bacterial elimination in the liver, by increasing the phagocytic and bactericidal activities of liver F4/80+CD11b+ recruited macrophages (Mφ), their CD206 expression and reactive oxygen species production. Quantitative PCR revealed that pioglitazone treatment enhanced gene expression of rate-limiting enzymes for glycolysis in hepatic CD11b+ cells (including neutrophils and recruited Mφ), and their improved phagocytic and bactericidal activities were abolished by glycolysis inhibiting reagents. These findings present the possibility that pioglitazone strengthens the phagocytic and bactericidal activities of liver recruited Mφ and that these immunological activities are closely associated with their glucose catabolism. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are professional Ag-presenting cells that play a critical role in both innate and adaptive immune responses. DCs recognize and respond to bacteria through multiple PRRs, including TLRs. Heat shock protein gp96/grp94 is a master essential chaperone for TLRs in the endoplasmic reticulum. We generated DC-specific gp96-knockout (KO) mice and showed that gp96 KO DCs were unable to respond to multiple TLR ligands. TLR-mediated hyperinflammatory response can lead to sepsis. However, the roles of neither DCs nor the DC-intrinsic gp96 in the process are completely understood. In a LPS-induced sepsis model, we hereby found that deletion of gp96 in DCs significantly reduced serum TNF-α levels and improved survival. Furthermore, using the well-defined polymicrobial sepsis model of cecal ligation and puncture, we found that DC-specific ablation of gp96 improved survival with significantly attenuated liver and renal injuries, decreased circulating inflammatory cytokines, altered DC maturation and activation, and increased serum Ig. Collectively, we demonstrate that deletion of gp96 in DCs is beneficial in protecting mice against sepsis induced by both endotoxemia and polymicrobial infections. We conclude that targeting gp96 in DCs may provide a potential novel approach for reducing the morbidity and mortality of sepsis. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2−/− mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1β secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1β secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling. [ABSTRACT FROM AUTHOR]

Lipoteichoic acid (LTA) of Enterococcus faecalis is a potent stimulator of inflammatory responses, but the effects of E. faecalis LTA on osteoclastogenesis remains far from well understood. This study showed that E. faecalis LTA significantly inhibited osteoclastogenesis of wild type murine bone marrow-derived macrophages (BMMs) in the presence of a high dose of RANKL, while the inhibition of osteoclastogenesis by E. faecalis LTA was significantly removed in BMMs with deficient expression of the transcription factor RBP-J. In addition, a few small osteoclasts were generated in BMMs with only E. faecalis LTA stimulation, presumably due to the production of TNF-α and IL-6. Furthermore, both p38 and ERK1/2 MAPK signaling pathways were activated after 24 h of E. faecalis LTA treatment, but these signaling pathways were not activated after 6 d of treatment with RANKL in mature osteoclasts. In conclusion, E. faecalis LTA, which induces inflammatory response, could inhibit RANKL-induced osteoclastogenesis via RBP-J in BMMs. [ABSTRACT FROM AUTHOR]

Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis. [ABSTRACT FROM AUTHOR]

Platelets are the main players in thrombosis and hemostasis; however they also play important roles during inflammation and infection. Through their surface receptors, platelets can directly interact with pathogens and immune cells. Platelets form complexes with neutrophils to modulate their capacities to produce reactive oxygen species or form neutrophil extracellular traps. Furthermore, they release microbicidal factors and cytokines that kill pathogens and influence the immune response, respectively. Platelets also maintain the vascular integrity during inflammation by a mechanism that is different from classical platelet activation. In this review we summarize the current knowledge about how platelets interact with the innate immune system during inflammation and infection and highlight recent advances in the field. [ABSTRACT FROM AUTHOR]

The TLR2 agonist, dipalmitoyl lipopeptide (Pam2LP), has been used as an immune adjuvant without much success. Pam2LP is recognised by TLR2/6 receptors in humans and in mice. This study examined the proliferative activity of cytotoxic T lymphocytes (CTL) using mouse Ag-presenting dendritic cells (DCs) and OT-I assay system, where a library of synthetic Pam2LP was utilised from the Staphylococcus aureus database. Ag-specific CTL expansion and IFN-γ levels largely depended on the Pam2LP peptide sequence. The first Aa is cysteine (Cys), which has an active SH residue to bridge fatty acids, and the second and third Aa are hydrophilic or non-polar. The sequence structurally adapted to the residual constitution of the reported TLR2/6 pocket. The inactive sequence contained proline or leucine/isoleucine after the first Cys. Notably, no direct activation of OT-I cells was detected without DCs by stimulation with the active Pam2LP having the Cys-Ser sequence. MyD88, but not TICAM-1 or IFN pathways, in DCs participates in DC maturation characterised by upregulation of CD40, CD80 and CD86. Hence, the active Pam2LPs appear suitable for dimeric TLR2/6 on DCs, resulting in induction of DC maturation. [ABSTRACT FROM AUTHOR]

Activation of peroxisome proliferator-activated receptor (PPAR)-b/d reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR-β/δ -agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03mg/ kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-β/δ -antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-γ but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post-CLP systemic cytokine response and coagulation systems. [ABSTRACT FROM AUTHOR]