Proinflammatory State Research Articles

Exploring the Complex Relationship Between Psychosocial Stress and the Gut Microbiome: Implications for Inflammation and Immune Modulation.

There is growing interest in understanding the complex relationship between psychosocial stress and the human gastrointestinal microbiome (GIM). This review explores the potential physiological pathways connecting these two and how they contribute to a pro-inflammatory environment that can lead to the development and progression of the disease. Exposure to psychosocial stress triggers the activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary axis (HPA), leading to various physiological responses essential for survival and coping with the stressor. However, chronic stress in susceptible individuals could cause sustained activation of HPA and SNS, leading to immune dysregulation consisting of redistribution of NK cells in the bloodstream, decreased function of T and B cells, and elevation of proinflammatory cytokines such as IL-1, IL-6, TNF-ɑ, IFN-γ. It also leads to disruption of the GIM composition and increased intestinal barrier permeability, contributing to GIM dysbiosis. The GIM dysbiosis and elevated cytokines can lead to reciprocal effects and further stimulate the HPA and SNS, creating a positive feedback loop that results in a pro-inflammatory state underlying the pathogenesis and progression of stress-associated cardiovascular, gastrointestinal, autoimmune, and psychiatric disorders. Understanding these relationships is critical for developing new strategies for managing stress-related health disorders.

Early transcriptomic changes at the skin interface during Powassan virus transmission by Ixodes scapularis ticks

IntroductionPowassan virus (POWV), a vector-borne pathogen transmitted by Ixodes ticks in North America, is the causative agent of Powassan encephalitis. As obligate hematophagous organisms, ticks transmit pathogens like POWV at the tick bite site, specifically during the initial stages of feeding. Tick feeding and salivary factors modulate the host’s immunological responses, facilitating blood feeding and pathogen transmission. However, the mechanisms of immunomodulation during POWV transmission remain inadequately understood. In this study, we investigated the global cutaneous transcriptomic changes associated with tick bites during POWV transmission.MethodsWe collected skin biopsies from the tick attachment sites at 1, 3, and 6 h after feeding by POWV-infected and uninfected ticks, followed by RNA sequencing of these samples. Differentially expressed genes were analyzed for pathway enrichment using gene ontology and pathway enrichment analyses.ResultsOur findings reveal that tick feeding alone significantly impacts the skin transcriptome within the first 1 to 3 h of tick attachment. Although early POWV transmission induces minimal changes in the local environment, a pronounced shift toward a proinflammatory state is observed 6 h after tick attachment, characterized by neutrophil recruitment and interleukin signaling.DiscussionThese transcriptomic data elucidate the dynamic changes at the tick bite site, transitioning from changes that assist blood meal acquisition to a proinflammatory phase that may facilitate viral dissemination.

A One Stone Three Birds Paradigm of Photon‐Driven Pyroptosis Dye for Amplifying Tumor Immunotherapy

AbstractActivating the pyroptosis pathway of tumor cells by photodynamic therapy (PDT) for immunogenic cell death (ICD) is considered a valid strategy in pursuit of antitumor immunotherapy, but it remains a huge challenge due to the lack of reliable design guidelines. Moreover, it is often overlooked that conventional PDT can exacerbate the development of tumor immunosuppressive microenvironment, which is apparently unfavorable to clinical immunotherapy. The endoplasmic reticulum's (ER) pivotal role in cellular homeostasis and its emerging link to pyroptosis have galvanized interest in ER‐centric imaging and therapeutics. Herein, using the targeted group‐assisted strategy (TAGS), an intriguing cyclooxygenase‐2‐targeted photodynamic conjugate, Indo‐Cy, strategically created, which exploits the enzyme's overabundance in the tumoral ER, especially under proinflammatory hypoxic conditions. This conjugate, with its highly precise ER imaging, embodies a trifunctional strategy: i) innovating an electron transfer mechanism, converting the hemicyanine moiety into an oxygen‐independent type I photosensitizer, thereby navigating around the hypoxia constraints of traditional PDT; ii) executing precise ER‐targeted PDT, amplifying caspase‐1/GSDMD‐mediated pyroptosis for ICD; 3) attenuating immunosuppressive pathways by inhibiting cyclooxygenase‐2 downstream factors, including HIF‐1α, PGE2, and VEGF. Indo‐Cy's multimodal approach potently induces in vivo tumor pyroptosis and bolsters antitumor immunity, underscoring cyclooxygenase‐2‐targeted dyes' potential as a versatile oncotherapeutics.

The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation

Neuroinflammation is a blanket term that describes the body’s complex inflammatory response in the central nervous system (CNS). It encompasses a phenotype shift to a proinflammatory state, the release of cytokines, the recruitment of peripheral immune cells, and a wide variety of other processes. Neuroinflammation has been implicated in nearly every major CNS disease ranging from Alzheimer’s disease to brain cancer. Understanding and modeling neuroinflammation is critical for the identification of novel therapeutic targets in the treatment of CNS diseases. Unfortunately, the translation of findings from non-human models has left much to be desired. This review systematically discusses the role of human pluripotent stem cell (hPSC)-derived glia and supporting cells within the CNS, including astrocytes, microglia, oligodendrocyte precursor cells, pericytes, and endothelial cells, to describe the state of the field and hope for future discoveries. hPSC-derived cells offer an expanded potential to study the pathobiology of neuroinflammation and immunomodulatory cascades that impact disease progression. While much progress has been made in the development of models, there is much left to explore in the application of these models to understand the complex inflammatory response in the CNS.

Gut microbiome dysbiosis is not associated with portal vein thrombosis in patients with end-stage liver disease: a cross-sectional study.

Portal vein thrombosis (PVT) is a common complication in patients with end-stage liver disease (ESLD). The portal vein in ESLD patients is proposedly an inflammatory vascular bed due to translocation of endotoxins and cytokines from the gut. We hypothesized that a pro-inflammatory gut microbiome and elevated trimethylamine N-oxide (TMAO), a driver of thrombosis, may contribute to PVT development. We investigated whether gut microbiome diversity, bacterial species, metabolic pathways, and TMAO levels are associated with PVT in ESLD patients. Fecal samples, plasma samples and data from ESLD patients and healthy controls were collected through the TransplantLines Biobank and Cohort Study. PVT was defined as a thrombus in the portal vein within a year prior to or after fecal sample collection. Fecal samples were analyzed using Shotgun Metagenomic Sequencing, and TMAO levels were measured in plasma using a Vantera® Clinical Analyzer. 102 ESLD patients, of which 23 with PVT, and 246 healthy controls were included. No significant difference in gut microbiome diversity was found between patients with PVT and without PVT (P=0.18). Both ESLD groups had significantly lower alpha-diversity compared with controls. Bacteroides fragilis and three Clostridiales species were increased in patients with PVT compared to without PVT. TMAO levels between the three groups were not significantly different. We observed profound differences in gut microbiota between ESLD patients and controls, but minimal differences between ESLD patients with or without PVT. In our cohort, a gut-derived pro-inflammatory state was not associated with presence of PVT in ESLD patients.

In Situ Proefferocytosis Microspheres as Macrophage Polarity Converters Accelerate Osteoarthritis Treatment.

Efferocytosis in macrophages typically engages an anti-inflammatory positive feedback regulatory mechanism. In osteoarthritis (OA), characterized by imbalanced inflammatory homeostasis, the proinflammatory state of macrophages in the immune microenvironment can be reversed through enhanced efferocytosis. This study develops an in situ proefferocytosis hydrogel microsphere (macrophage polarity converter, H-C@IL) for OA treatment. Immunoliposomes (IL), CD16/32 antibody-modified clodronate liposomes, are initially prepared using the Re-emulsion method. Then, the IL is loaded into CCL19-modified HAMA microspheres through microfluidic technology. In vitro, H-C@IL can specifically recruit M0 and M1 macrophages via CCL19, induce apoptosis in M1 macrophages through secondary targeting with IL, and provide "Find/Eat-me" signals to enhance in situ efferocytosis. Additionally, it promotes macrophage polarization toward the M2 phenotype. In vivo, behavioral, imaging, and histological analyses demonstrate that H-C@IL effectively facilitates macrophage polarization toward M2, inhibits inflammation, and promotes cartilage regeneration. Mechanistically, H-C@IL enhances efferocytosis by activating proteins such as PROS1 and TIMD4 in M0 macrophages. Concurrently, signaling pathways, including PQLC2-Arg-Rac1 and Pbx1/IL-10, are activated to drive the polarization of macrophages from M0 to M2. In summary, H-C@IL promotes M0 macrophage efferocytosis in situ, facilitates macrophage polarization toward M2, restores inflammatory homeostasis, and promotes cartilage regeneration, offering a comprehensive treatment strategy for OA.

Characterizing Microglial Signaling Dynamics During Inflammation Using Single-Cell Mass Cytometry.

Microglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post-translational changes. In this study, we utilized time-resolved single-cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics-lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 h. Cultures were stained with a panel of 33 metal-conjugated antibodies targeting signaling and identity markers. High-dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical reactivity markers CD40 and CD86 at later time points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single-cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro-inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.

Analysis of fatty acid-derived lipids in critically ill patients after cardiac surgery yields novel pathophysiologically relevant mediators with possible relevance for systemic inflammatory reactions

IntroductionCritically ill patients suffer from a wide variety of clinical events, most of them leading to pro-inflammatory states such as sepsis or simply as consequence of major surgery. Many of these patients develop forms of acute kidney injury, heart or acute liver failure during intensive care. Lipid signaling is critically involved in triggering systemic inflammation processes, pain and vascular tone. We therefore hypothesized that fatty-acid-derived lipid mediators might be regulated during inflammatory stages and other clinical events in critically ill patients and might serve as potential biomarker candidates.Methods and study designUsing liquid chromatography-tandem mass spectrometry (LC-MS/MS), we determined the levels of 53 lipid mediators in plasma from nine patients. These patients were hospitalized at Frankfurt University Hospital’s intensive care unit (ICU) after cardiac surgery. Inflammatory stages were illustrated over time using clinically established biomarkers such as interleukin-6 (IL-6) and leukocyte count. Normal range values of the lipids were obtained from healthy volunteers.ResultsPlasma levels clearly outside the normal range were observed for 22 of 53 lipid mediators, of which 13 were increased (including ceramides Cer (d18:0/18:0), Cer (d18:1/16:0), Cer (d18:1/18:1), glucosyl-ceramide GluCer (d18:1/24:1), lactosylceramide LacCer (d18:1/18:0), and LacCer (d18:1/24:1), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), 11,12- and 14,15-DHET and 1- and 2-arachidonoyl glycerol (1-AG and 2-AG), Sphingosine SPH (d18:1) and 20-HETE. Furthermore, nine lipids were decreased (Cer (d18:1/24:0), LacCer (d18:1/16:0), LacCer (d18:1/24:0), sphingosine-1-phosphate S1P (d18:1), S1P (d18:0), the lysophosphatidic acids LPA (16:0), LPA (18:0), LPA (18:1) and 9-HODE. Among increased lipids, the remarkable changes in 1-AG, 2-AG, and to a lower extent of 6-keto-PGF1-alpha plasma levels showed a certain agreement with inflammatory phases. Furthermore, 6-keto-PGF1alpha had its peak shortly before initiation of continuous veno-venous hemodialysis (at least in 5 of the observed patients), 2-AG was elevated in all our nine patients during (right) heart failure in the context of either re-opening patient’s chest, implementation of veno-arterial ECMO or at least while significantly increasing the amount of catecholamines.DiscussionIn this pilot trial we identified several evaluated lipids in critically ill patients representing either potentially (patho-) physiologically relevant mediators of the pro-inflammatory processes and during heart failure or possible markers preceding veno-venous hemodialysis.

Dietary caloric input and tumor growth accelerate senescence and modulate liver and adipose tissue crosstalk

Metabolic alterations are related to tumorigenesis and other age-related diseases that are accelerated by “Westernized” diets. In fact, hypercaloric nutrition is associated with an increased incidence of cancers and faster aging. Conversely, lifespan-extending strategies, such as caloric restriction, impose beneficial effects on both processes. Here, we investigated the metabolic consequences of hypercaloric-induced aging on tumor growth in female mice. Our findings indicate that a high-fat high-sucrose diet increases tumor growth mainly due to the boosted oxidation of glucose and fatty acids. Consequently, through an increased expression of lactate, IGFBP3, and PTHLH, tumors modulate liver and white adipose tissue metabolism. In the liver, the induced tumor increases fibrosis and accelerates the senescence process, despite the lower systemic pro-inflammatory state. Importantly, the induced tumor induces the wasting and browning of white adipose tissue, thereby reversing diet-induced insulin resistance. Finally, we suggest that tumor growth alters liver-adipose tissue crosstalk that upregulates Fgf21, induces senescence, and negatively modulates lipids and carbohydrates metabolism even in caloric-restricted-fed mice.

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice.

The role of immune cells in neurodegeneration remains incompletely understood. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. Accumulation of misfolded tau proteins are a hallmark of neurodegenerative diseases. The role of MAIT cells in tau-related neuroinflammation and neurodegeneration, however, remains unclear. Here we report that the meninges of P301 mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1 -/- P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1 +/+ P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1 -/- P301S mice. Meningeal barrier integrity was compromised in Mr/ -/- P301S mice, but not in control Mr1 +/+ P301S mice. A distinctive microglia subset with proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1 -/- P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related with ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1 -/- P301S mice. Together, our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

Mesenchymal Stromal Cell (MSC) Functional Analysis-Macrophage Activation and Polarization Assays.

Stem cell-based therapies have evolved to become a key component of regenerative medicine approaches to human pathologies. Exogenous stem cell transplantation takes advantage of the potential of stem cells to self-renew, differentiate, home to sites of injury, and sufficiently evade the immune system to remain viable for the release of anti-inflammatory cytokines, chemokines, and growth factors. Common to many pathologies is the exacerbation of inflammation at the injury site by proinflammatory macrophages. An increasing body of evidence has demonstrated that mesenchymal stromal cells (MSCs) can influence the immunophenotype and function of myeloid lineage cells to promote therapeutic effects. Understanding the degree to which MSCs can modulate the phenotype of macrophages within an inflammatory environment is of interest when considering strategies for targeted cell therapies. There is a critical need for potency assays to elucidate these intercellular interactions in vitro and provide insight into potential mechanisms of action attributable to the immunomodulatory and polarizing capacities of MSCs, as well as other cells with immunomodulatory potential. However, the complexity of the responses, in terms of cell phenotypes and characteristics, timing of these interactions, and the degree to which cell contact is involved, have made the study of these interactions challenging. To provide a research tool to study the direct interactions between MSCs and macrophages, we developed a potency assay that directly co-cultures MSCs with naïve macrophages under proinflammatory conditions. Using this assay, we demonstrated changes in the macrophage secretome and phenotype, which can be used to evaluate the abilities of the cell samples to influence the cell microenvironment. These results suggest the immunomodulatory effects of MSCs on macrophages while revealing key cytokines and phenotypic changes that may inform their efficacy as potential cellular therapies. Key features • The protocol uses monocytes differentiated into naïve macrophages, which are loosely adherent, have a relatively homogeneous genetic background, and resemble peripheral blood mononuclear cells-derived macrophages. • The protocol requires a plate reader and a flow cytometer with the ability to detect six fluorophores. • The protocol provides a quantitative measurement of co-culture conditions by the addition of a fixed number of freshly thawed or culture-rescued MSCs to macrophages. • This protocol uses assessment of the secretome and cell harvest to independently verify the nature of the interactions between macrophages and MSCs.

Genetic predisposition to high circulating levels of interleukin 6 and risk for Alzheimer's disease. Discovery and replication.

Aging is accompanied by immune dysregulation, which has been implicated in Alzheimer's disease (AD) pathogenesis. Individuals who are genetically predisposed to elevated levels of proinflammatory mediators might be at increased risk for AD. To investigate whether genetic propensity for higher circulating levels of interleukin 6 (IL-6) is associated with AD risk. We analyzed data from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Mean follow-up was 2.9 (SD, 0.8) years. Baseline assessment was from 11/2009 to 11/2016, and cognitive follow-up from 01/2013 to 07/2019. Associations of interest were also examined in the UK Biobank (UKB) for replication purposes (mean follow-up was 12.9 (SD, 2.4) years; baseline assessment was from 12/2006 to 10/2010). Population-based study. The HELIAD sample included 622 participants ≥65 years of age without baseline dementia or amnestic mild cognitive impairment (aMCI-the prodromal stage of AD). The UKB sample included 142,637 participants ≥60 years of age without prevalent dementia. Genetic predisposition to elevated circulating levels of IL-6 was estimated using a polygenic risk score (PRS), calculated based on the summary statistics of a current GWAS meta-analysis. AD and MCI diagnoses were based on standard clinical criteria [HELIAD], or hospital records and death registry data [UKB]. Associations with AD or aMCI incidence [HELIAD] and AD incidence [UKB] were examined with Cox regression models. In HELIAD, mean age was 73.4 (SD, 5.0) years; 363 (58%) women. An increase in IL-6 PRS by 1 standard deviation unit (SDU) was associated with up to a 43% increase in the risk for incident AD/aMCI (HRGWAS significance threshold of 0.01, 1.43 [95%CI, 1.14 - 1.80]). In UKBB, mean age was 64.2 (SD, 2.8) years; 73,707 (52%) women. A 1 SDU increase in IL-6 PRS was associated with up to an 8% increase in the risk for incident AD (HRGWAS significance threshold of 0.2, 1.08 [95%CI, 1.04 - 1.12]). Genetic predisposition to higher circulating levels of IL-6 was associated with an increased risk for AD, supporting the role of IL-6-related pathways in AD pathogenesis, and suggesting that genetic predisposition to proinflammatory states might trigger or accelerate AD-related neuropathology.

Small Extracellular Vesicles Derived from Lipopolysaccharide-Treated Stem Cells from the Apical Papilla Modulate Macrophage Phenotypes and Inflammatory Interactions in Pulpal and Periodontal Tissues.

Inflammation significantly influences cellular communication in the oral environment, impacting tissue repair and regeneration. This study explores the role of small extracellular vesicles (sEVs) derived from lipopolysaccharide (LPS)-treated stem cells from the apical papilla (SCAP) in modulating macrophage polarization and osteoblast differentiation. SCAPs were treated with LPS for 24 h, and sEVs from untreated (SCAP-sEVs) and LPS-treated SCAP (LPS-SCAP-sEVs) were isolated via ultracentrifugation and characterized using transmission electron microscopy, Western blot, and Tunable Resistive Pulse Sensing. LPS-SCAP-sEVs exhibited characteristic exosome morphology (~100 nm diameter) and expressed vesicular markers (CD9, CD63, CD81, and HSP70). Functional analysis revealed that LPS-SCAP-sEVs promoted M1 macrophage polarization, as evidenced by the increased pro-inflammatory cytokines (IL-6 and IL-1β) and the reduced anti-inflammatory markers (IL-10 and CD206), while impairing the M2 phenotype. Additionally, LPS-SCAP-sEVs had a minimal impact on SCAP metabolic activity or osteogenic gene expression but significantly reduced mineralization capacity in osteogenic conditions. These findings suggest that sEVs mediate the inflammatory interplay between SCAP and macrophages, skewing macrophage polarization toward a pro-inflammatory state and hindering osteoblast differentiation. Understanding this sEV-driven communication axis provides novel insights into the cellular mechanisms underlying inflammation in oral tissues and highlights potential therapeutic targets for modulating extracellular vesicle activity during acute inflammatory episodes.

The Interplay Between High Cumulative Doses of Radioactive Iodine and Type 2 Diabetes Mellitus: A Complex Cardiovascular Challenge.

Starting from the metabolic profile of type 2 diabetes mellitus (T2DM), we hypothesized that the mechanisms of ¹³¹I-induced cardiotoxicity differ between patients diagnosed with differentiated thyroid cancer (DTC) with/without T2DM, with metformin potentially acting as a cardioprotective agent by mitigating inflammation in patients with T2DM. To address this hypothesis, we quantified, using ELISA, the serum concentration of several key biomarkers that reflect cardiac injury (NT-proBNP, NT-proANP, ST2/IL-33R, and cTn I) in 74 female patients with DTC/-T2DM and 25 with DTC/+T2DM treated with metformin. All patients received a cumulative oral dose of 131I exceeding 150 mCi (5.55 GBq) over approximately 53 months. Our results showed the following: (i) In DTC/-T2DM patients, high-cumulative 131I doses promote a pro-inflammatory state that accelerates the development of cardiotoxicity. Monitoring NT-proBNP, ST2/IL-33R, and cTn I in these patients may help identify those at risk of developing cardiac complications. (ii) In patients with DTC/+T2DM, high-cumulative 131I doses lead to the release of NT-proANP (r = 0.63), which signals that the atria are under significant stress. (iii) In patients with DTC/+T2DM, metformin suppresses inflammation, leading to a dose-dependent reduction in cTn I (r = -0.59). Monitoring cTn I and NT-proANP, and considering the use of metformin as part of the therapeutic strategy, could help manage cardiotoxicity in T2DM patients undergoing 131I therapy.

Proinflammatory cytokines, chemokine CXCL17 and heat shock proteins in osteoarthritis of the knee joint

Osteoarthritis (OA), a common multifactorial disease of musculoskeletal system, is one of the leading causes of disability in the population. One of the most important pathogenetic factors of OA is a shift of cytokine profile towards pro-inflammatory state. Their increased levels lead to dysfunction of cartilage tissue cells with its damage. Purpose of the present study was to evaluate diagnostic significance of the most important cytokine and chemokine levels involved in pathogenesis of OA. The study involved 50 patients undergoing inpatient treatment at the “Hospital for War Veterans” (Vladivostok) with an established OA of the knee joints. The following mediators involved in the development of inflammation have been determined: interleukins IL-1â, IL-6, chemokine CXCL17, tumor necrosis factor TNFá and heat shock proteins HSP27, HSP70 in blood serum of patients being analyzed by ELISA test systems. It has been shown that the levels of interleukins IL-1â and IL-6, TNFá and CXCL17 in patients with OA exceeded those for healthy individuals. The levels of cytokines IL- 1â, IL-6, chemokine CXCL17 and TNFá in blood serum of OA patients were 7.4 (6.4-8.9), 33.7 (26.5-68.4); 33.8 (29.8- 61.0) and 6.5 (4.94-8.59) pg/ml, respectively, thus significantly exceeding the values for healthy person s (1.3 (1.2-1.4), 5.8 (4.2-6.3), 24.9 (19, 1-29.9) and 2.7 (2.1-3.1) pg/ml, p 0.05). In OA patients, the concentration of TNFá had a direct relationship with the chemokine CXCL17 (r = 0.83, p 0.05). The concentrations of heat shock proteins HSP27, HSP70 and their ratio were significantly lower in patients with OA compared to the control group (respectively: z = -3.06, p = 0.002; z = -4.41, p = 0.00001; z = -2.05, p = 0.04), thus allowing us to suggest the tolerance of chondrocytes to the influence of cytokines. At the same time, the concentration of HSP70 decreased as the disease progressed, while the level of HSP27 did not change significantly. Thus, determining the level of systemic intercellular mediators enables usage of these indexes as potential biochemical markers for predicting severity of the disease and assessing their fundamental role in pathogenesis of knee OA.

Glucocorticoid-Dependent Retinal Degeneration and Vision Impairment in Mice Susceptible to Prenatal Stress-Induced Behavioral Abnormalities.

Chronic exposure to prenatal stress can impair neurogenesis and lead to irreversible cognitive and neuropsychiatric abnormalities in offspring. The retina is part of the nervous system; however, the impacts of prenatal stress on retinal neurogenesis and visual function remain unclear. This study examined how elevated prenatal glucocorticoid levels differentially affect retinal development in the offspring of pregnant mice exposed to chronic unpredictable mild stress (CUMS). Offspring were classified into control, stress-resilient, and stress-susceptible groups based on behavioral tests assessing spatial memory and depression-like behaviors. The stress-susceptible group exhibited significantly altered synaptogenesis, reduced ganglion cell development, decreased retinal thickness, and visiual impairment. These mice also showed a pervasive transformation of retinal astrocytes into a proinflammatory A1-like reactive state, evidenced by increased GFAP and decreased STAT3 expression levels. This astrocyte phenotype shift coincided with disruptions in neurogenesis and synaptic formation. Furthermore, prenatal exposure to exogenous corticosterone confirmed that the effects of prenatal stress are mediated by glucocorticoid-induced retinal neurodegeneration. Our findings suggest that elevated prenatal glucocorticoid levels trigger a series of neurodevelopmental disturbances leading to retinal neurodegeneration and vision impairment. This research highlights the impact of prenatal stress on retinal development and visual health, suggesting new avenues for understanding and potentially mitigating the negative effects of early-life stress on neurodevelopment.

Does novel coronavirus infection increase the risk of chronic systemic hyperinflammation and low-grade systemic inflammation in patients with pulmonary tuberculosis?

The development of new coronavirus infectious disease (COVID-19) is associated with an increase in the pro-inflammatory and pro-thrombotic potential of microvascular endothelium. A specific feature of SARS-CoV-2 infection is the post-COVID syndrome that is characterised by long-term impairment of various organs and systems. The immune pathogenesis of post-COVID syndrome in patients with pulmonary tuberculosis requires special attention due to their baseline pro-inflammatory status. The objective of this study was to evaluate the effect of novel coronavirus infection on the risk of chronic systemic hyper-inflammation and low-grade systemic inflammation in patients with pulmonary tuberculosis. Two main groups consisted of patients with pulmonary tuberculosis who had survived COVID-19 (mild form) 3 months ago, or at earlier terms, including the subjects with post-COVID symptoms and those free of these symptoms. The comparison group included patients with pulmonary tuberculosis without a history of COVID-19. The control group was presented by healthy blood donors. Concentrations of IL-6, IL-10, tumor necrosis factor alpha (TNFá), D-dimers, troponin I, cortisol, and endothelin I (ET-I) were measured in patients’ plasma by immunoassay technique. On the basis of these markers, we calculated integral indices of systemic inflammatory response (SIR) – the levels of reactivity (RL), and chronic systemic hyper-inflammation (ChSI). Low-grade systemic inflammation (LGSI) was diagnosed in absence of ChSI, but in cases of simultaneous increase of D-dimer levels 250 ng/ml and ET-I levels 90 pg/ml in the patient. The most prevalent symptoms of post-COVID in patients with pulmonary tuberculosis were tachycardia, arthralgia, and chronic fatigue syndrome, which correspond to the population-wide data. By all empirical parameters, the groups of tuberculosis patients were comparable to each other (p 0.05) and significantly differed from control group. However, evaluation of integral indexes is more crucial for assessing the ‘systemic’ origin of the process. Thus, 23-50% of patients with pulmonary tuberculosis developed subcritical SIR (RL = 1-2), being a feature of ChSI in 7.1-13.6% of cases (both in COVID-19 reconvalescents and non-COVID-19 patients). Meanwhile, all patient groups did not show significant difference in the frequency of LGSI and endothelial dysfunction (p 0.05). However, there was a trend towards an increase of these scores in the following sequence: tuberculosis without COVID-19 – tuberculosis + COVID-19 – tuberculosis + COVID-19 + post-COVID syndrome. Most patients with pulmonary tuberculosis are not characterized by the development of chronic systemic hyperinflammation. LGSI is the most probable feature of general pathology in tuberculosis infection. Tuberculosis infection sufficiently contributes to the development of LGSI, since the frequency and severity of LGSI and its individual manifestations are independent on the new coronavirus infection and signs of post-COVID syndrome.

Inflammation remains a dynamic component of portal hypertension in regressive alcohol-related cirrhosis.

Portal hypertension (PH) resulting from static and dynamic intrahepatic changes drives liver-related complications even after removing the underlying aetiological factor. We investigated the impact of inflammation on the dynamic component of PH during disease regression in animal models of toxin-induced cirrhosis and patients with alcohol-related cirrhosis. In mice, cirrhosis was induced via toxin application for 12weeks followed by toxin-withdrawal allowing for one or 2weeks of regression. Furthermore, 128 patients with alcohol-related cirrhosis and alcohol abstinence undergoing same-day hepatic venous pressure gradient (HVPG) and liver stiffness measurement (LSM) were included. The influence of inflammation on the dynamic PH component was assessed using linear models. Specifically, we explored proinflammatory changes in mice/patients in whom the measured portal pressure (PP)/HVPG was significantly higher than the PP/HVPG expected from the static PH component (histological collagen proportionate area [CPA; %] in mice, LSM in patients). In mice, toxin discontinuation induced a significant decrease in PP, CPA, histological hepatic inflammation and hepatic expression of proinflammatory genes (Tnfa, Il6, Cxcl1, Mcp1; all p<0.05 for one/2week regression vs. peak disease). Similarly, prolonged abstinence in alcohol-related cirrhosis was linked to lower HVPG/LSM and longer abstinence was correlated to lower C-reactive protein (CRP), IL-6, immunoglobulin A (IgA) and IgG levels (all p<0.05). Nevertheless, the persistence of a low-grade proinflammatory state during regression was linked to a higher PP/HVPG than expected from static PH components. In regressive mice, higher hepatic proinflammatory gene expression (Tnfa, Il6, Il1b; all p<0.05) was linked to higher-than-expected PP. Similarly, higher CRP, IL-6, IgA and IgG and lower complement factor C3c (all p<0.05) were associated with higher-than-expected HVPG in abstinent patients with alcohol-related cirrhosis. Although removing the underlying aetiological factor resulted in significant improvements, a persistent hepatic proinflammatory environment remained a key driver of the dynamic PH component in regressive liver disease. NCT03267615.

Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis

Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella’s metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.

Trastornos neuropsiquiátricos asociados al Covid persistente

Persistent COVID (PC) is the term used to describe a multisystemic and multifactorial entity, which follows acute SARS-CoV-2 infection. Symptoms must persist for three months or more to define this disorder. The clinical manifestations are variable and nonspecific, but have a great impact on the quality of life of patients. Neuropsychiatric symptoms are commonly reported in CP, mostly chronic fatigue, cognitive disorders, attention disorders, among others. The pathophysiological mechanisms are not fully known, but the most described are hypoxia related neuronal damage, microvascular lesions, a persistent proinflammatory state, activation of latent viral infections, and alteration of the blood-brain barrier. There are no specific complementary tests to confirm the diagnosis of CP. There is also no specific treatment to date and most therapies are aimed at relieving symptoms and improving quality of life. This article provides a comprehensive bibliographic review of the most common neuropsychiatric manifestations of CP, including its probable pathophysiological mechanisms and the therapies proposed to date.