Local Cell Populations Research Articles

Perivascular Adipose Tissue Becomes Pro-Contractile and Remodels in an IL10-/- Colitis Model of Inflammatory Bowel Disease.

Inflammatory Bowel Diseases (IBDs) are associated with aberrant immune function, widespread inflammation, and altered intestinal blood flow. Perivascular adipose tissue (PVAT) surrounding the mesenteric vasculature can modulate vascular function and control the local immune cell population, but its structure and function have never been investigated in IBD. We used an IL10-/- mouse model of colitis that shares features with human IBD to test the hypothesis that IBD is associated with (1) impaired ability of PVAT to dilate mesenteric arteries and (2) changes in PVAT resident adipocyte and immune cell populations. Pressure myography and electrical field stimulation of isolated mesenteric arteries show that PVAT not only loses its anti-contractile effect but becomes pro-contractile in IBD. Quantitative immunohistochemistry and confocal imaging studies found significant adipocyte hyperplasia and increased PVAT leukocytes, particularly macrophages, in IBD. PCR arrays suggest that these changes occur alongside the altered cytokine and chemokine gene expression associated with altered NF-κB signaling. Collectively, these results show that the accumulation of macrophages in PVAT during IBD pathogenesis may lead to local inflammation, which ultimately contributes to increased arterial constriction and decreased intestinal blood flow with IBD.

Immunological memory diversity in the human upper airway.

The upper airway is an important site of infection, butimmune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases1-4. Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory Bcells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (TRM)cell and B (BRM) cellpopulations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific BRMcells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA+ memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4+ TRM cellsand CD8+ TRM cellswere identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans.

Derivation and travelling wave analysis of phenotype-structured haptotaxis models of cancer invasion

AbstractWe formulate haptotaxis models of cancer invasion wherein the infiltrating cancer cells can occupy a spectrum of states in phenotype space, ranging from ‘fully mesenchymal’ to ‘fully epithelial’. The more mesenchymal cells are those that display stronger haptotaxis responses and have greater capacity to modify the extracellular matrix (ECM) through enhanced secretion of matrix-degrading enzymes (MDEs). However, as a trade-off, they have lower proliferative capacity than the more epithelial cells. The framework is multiscale in that we start with an individual-based model that tracks the dynamics of single cells, which is based on a branching random walk over a lattice representing both physical and phenotype space. We formally derive the corresponding continuum model, which takes the form of a coupled system comprising a partial integro-differential equation for the local cell population density function, a partial differential equation for the MDE concentration and an infinite-dimensional ordinary differential equation for the ECM density. Despite the intricacy of the model, we show, through formal asymptotic techniques, that for certain parameter regimes it is possible to carry out a detailed travelling wave analysis and obtain invading fronts with spatial structuring of phenotypes. Precisely, the most mesenchymal cells dominate the leading edge of the invasion wave and the most epithelial (and most proliferative) dominate the rear, representing a bulk tumour population. As such, the model recapitulates similar observations into a front to back structuring of invasion waves into leader-type and follower-type cells, witnessed in an increasing number of experimental studies over recent years.

Palovarotene Action Against Heterotopic Ossification Includes a Reduction of Local Participating Activin A-Expressing Cell Populations.

Heterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes fibrodysplasia ossificans progressiva (FOP). Recently, we and others showed that activin A promotes both acquired and genetic HO, and in previous studies we found that the retinoid agonist palovarotene inhibits both HO forms in mice. Here, we asked whether palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a standard mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single-cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration (4 mg/kg/d/gavage) caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq data sets indicated that the drug had reduced interactions and cross-talk among local cell populations. To determine if palovarotene inhibited Inhba expression directly, we assayed primary chondrocyte cultures. Drug treatment inhibited their cartilaginous phenotype but not Inhba expression. Our data reveal that palovarotene markedly reduces the number of local Inhba-expressing HO-forming cell populations. The data broaden the spectrum of HO culprits against which palovarotene acts, accounting for its therapeutic effectiveness. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Peripheral (lung-to-brain) exposure to diesel particulate matter induces oxidative stress and increased markers for systemic inflammation

Combustion-derived air pollution is a complex environmental toxicant that has become a global health concern due to urbanization. Air pollution contains pro-inflammatory stimulants such as fine and ultrafine particulate matter, gases, volatile organic compounds, and metals. This study is focused on the particulate phase, which has been shown to induce systemic inflammation after chronic exposure due to its ability to travel to the lower airway, resulting in the activation of local immune cell populations, releasing acute phase reactants to mitigate ongoing inflammation. The systemic response is a potential mechanism for the co-morbidity associated with regions with high pollution and neuropathology. We exposed diesel particulate matter (DPM) to a pulmonary cell-derived in vitro model where macrophages mimic the diffusion of cytokines into the peripheral circulation to microglia. Alveolar macrophages (transformed U937) were inoculated with resuspended DPM in an acute exposure (24-h incubation) and analyzed for MCP-1 expression and acute phase reactants (IL-1β, IL-6, IL-8, and TNF-α). Post-exposure serum was collected and filtered from cultured alveolar macrophages, introduced to a healthy culture of microglial cells (HMC3), and measured for neurotoxic cytokines, oxidative stress, and pattern recognition receptors. After DPM exposure, the macrophages significantly upregulated all measured acute phase reactants, increased H2O2 production, and increased MCP-1 expression. After collection and filtration to remove excess particulates, microglia cells were incubated with the collected serum for 48 h to allow for cytokine diffusion between the periphery of microglia. Microglia significantly upregulated IL-6, IL-8, and oxidative stress with a moderate increase in IL-1β and TNF-α. As a marker required for signaling tissue damage, CD14 indicated that compared to direct inoculation of DPM, peripheral exposure resulted in the potent activation of microglia cells. The specificity and potency of the response have implications for neuropathology through lung-to-brain mechanisms after inhalation of environmental pollutants.

Molecular clocks, satellite cells, and skeletal muscle regeneration.

Skeletal muscle comprises approximately 50% of individual body mass and plays vital roles in locomotion, heat production, and whole body metabolic homeostasis. This tissue exhibits a robust diurnal rhythm that is under control of the suprachiasmatic nucleus (SCN) region of the hypothalamus. The SCN acts as a "central" coordinator of circadian rhythms, while cell-autonomous "peripheral" clocks are located within almost all other tissues/organs in the body. Synchronization of the peripheral clocks in muscles (and other tissues) together with the central clock is crucial to ensure temporally coordinated physiology across all organ systems. By virtue of its mass, human skeletal muscle contains the largest collection of peripheral clocks, but within muscle resides a local stem cell population, satellite cells (SCs), which have their own functional molecular clock, independent of the numerous muscle clocks. Skeletal muscle has a daily turnover rate of 1%-2%, so the regenerative capacity of this tissue is important for whole body homeostasis/repair and depends on successful SC myogenic progression (i.e., proliferation, differentiation, and fusion). Emerging evidence suggests that SC-mediated muscle regeneration may, in part, be regulated by molecular clocks involved in SC-specific diurnal transcription. Here we provide insights on molecular clock regulation of muscle regeneration/repair and provide a novel perspective on the interplay between SC-specific molecular clocks, myogenic programs, and cell cycle kinetics that underpin myogenic progression.

Violation of the vaginal microbiome and the risk of HIV infection in women

Women are the main population responsible for new HIV infections and the persistence of the HIV pandemic. The article provides a review of the current literature on the factors and mechanisms by which the vaginal microbiome can contribute to HIV infection. A key determinant of susceptibility to HIV infection is the composition of the vaginal microbiome, which can influence the local immune cell population and inflammation status. A low diversity microbial composition dominated by Lactobacillus crispatus does not increase the risk of HIV infection, and a high microbial diversity environment associated with bacterial vaginosis increases the risk of HIV infection. The female reproductive tract has a unique susceptibility to viral infection because tissue-specific immunity must elicit rapid antimicrobial responses to pathogens while maintaining sperm tolerance. It is important to note that the risk of HIV infection during sexual intercourse is multifactorial and is determined not only by the state of the microbiota of a woman’s genital tract, but also by the state of the partner’s microbiota, the viral load of HIV in the blood of the sexual partner, the presence/absence of anti-retroviral therapy in the partner, hormonal background and the phase of the menstrual cycle, which also affect the state of the microbiota.

Abstract 2892: A SREBF2-dependent genetic program drives a novel immunotolerant dendritic cell population that supports cancer progression

Abstract The development of immune responses to cancers are crucially dependent upon effective antigen cross-presentation by local dendritic cell (DC) populations. Indeed, DC-mediated T cell stimulation is essential for generating responses to anti-PD-1 immunotherapy. Tumors have been shown to hijack DC function in a process broadly known as tolerization. Despite the significant implications of this process on the modulation of anti-tumor immunity, the underlying mechanisms of this process remain unclear. We have identified a unique population of DCs in transgenic models of both melanoma and non-small cell lung cancer that arise within the tumor microenvironment and migrate to the draining lymph node (LN) tissues during the course of disease progression. RNAseq and flow cytometry studies revealed this DC population to exhibit a unique CD63 surface marker, enabling us to determine this subset to drive regulatory T cell (Treg) and TH2 expansion while suppressing conventional DC-mediated activation of CD8+ T cell responses, even at rare numbers. Additional transcriptional and metabolic studies showed these CD63+ DCs to be a subset of the previously identified 'mature DCs enriched in immunoregulatory molecules' (mregDC) population and to exhibit both enhanced activity of the mevalonate biosynthetic pathway as well as increased lipid stores and dependence on fatty acid oxidation. Inhibitor studies confirmed that mevalonate biosynthesis drives CD63+ mregDC-mediated immune tolerance while scATACseq studies have identified open regulatory elements in CD63+ mregDCs associated with key rate-limiting genes associated with the mevalonate pathway. Additional lineage analysis revealed the CD63+ mregDC population to evolve primarily from type 2 conventional DCs in vivo. Both DC-specific genetic deletion of the SREBF2 master transcription factor as well as SREBP2 pharmacologic inhibition suppresses melanoma progression while enhancing tumor CD8+ T cell infiltration. Adoptive transfer of CD63+ mregDCs enhances melanoma metastases and promotes the accumulation of Tregs in draining LN tissues. scRNAseq studies as well as spatial transcriptomic analysis has confirmed this same DC population in the sentinel LN tissues of melanoma patients. We propose that this novel DC subset represents a key target for augmenting anti-tumor immune responses and suppressing metastatic progression. Ongoing work is focused on dissecting the regulatory pathways dictating the transcriptional program of CD63+ mregDCs and developing a CD11c-CD63 bispecific depletion antibody for further pre-clinical testing. Citation Format: Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Georgia Beasley, Nagendra Yarla, Bala Thievanthiran, Brent A. Hanks. A SREBF2-dependent genetic program drives a novel immunotolerant dendritic cell population that supports cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2892.

PD04-12 RADIOTHERAPEUTIC TREATMENT OF PROSTATE CANCER CELLS PROMOTES THE RELEASE OF POTENTIALLY DELETERIOUS AND IMMUNOLOGICALLY ACTIVE EXTRACELLULAR VESICLES

You have accessJournal of UrologyCME1 Apr 2023PD04-12 RADIOTHERAPEUTIC TREATMENT OF PROSTATE CANCER CELLS PROMOTES THE RELEASE OF POTENTIALLY DELETERIOUS AND IMMUNOLOGICALLY ACTIVE EXTRACELLULAR VESICLES Ryan Molony, Sarah Kerns, Brian Marples, Emmanuel Oshodi, YuhChyau Chen, and Yi-Fen Lee Ryan MolonyRyan Molony More articles by this author , Sarah KernsSarah Kerns More articles by this author , Brian MarplesBrian Marples More articles by this author , Emmanuel OshodiEmmanuel Oshodi More articles by this author , YuhChyau ChenYuhChyau Chen More articles by this author , and Yi-Fen LeeYi-Fen Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: One in four prostate cancer (PCa) patients will develop late hematuria and other delayed bladder toxicities following radiotherapy (RT) through poorly understood mechanisms. Membrane-enclosed extracellular vesicles (EVs) are released from tumor and non-tumor cells at baseline, and their composition can change markedly in response to stimuli. The impact of RT-induced EV (RT-EV) release from PCa cells or other cell populations in the tumor microenvironment, including immune cells, have yet to be characterized. Here, we examined the dynamics and composition of RT-EVs released by PCa cells and immune cells in response to irradiation, and their association with bladder tissue toxicity. METHODS: Urinary EV cargo proteins in pre- and post-RT PCa patient samples were analyzed and compared by LC-MS/MS. The impact of RT on EV release kinetics was analyzed by nanoparticle tracking analysis. RT-EVs and naïve EVs were collected from PCa patients and PCa cells lines (C4-2 and LNCaP). Their mechanistic effects on normal SV-HUC urothelial cells were assessed, including cellular viability, reactive oxygen species (ROS) production, and cytokine release. The effects of RT-EVs and RT on the activation of immune cell populations were monitored by treating Jurkat T cells or HL-60-derived neutrophils with RT-EVs or irradiating these cells and evaluating activation, cytokine release, and ROS production. RESULTS: The post-RT urinary EVs of a PCa patient who later developed hematuria were enriched for potentially caustic neutrophil-associated proteins relative to EVs from a hematuria-free patient. RT significantly enhanced the release of EVs from PCa cell lines and neutrophils, and these RT-EVs or direct irradiation promoted increased ROS production by HL-60 neutrophils, Jurkat T cells, and SV-HUC urothelial cells while also increasing interleukin (IL)-1β release from SV-HUC cells consistent with the induction of a damage-associated innate immune response. CONCLUSIONS: These results suggest RT can provoke the release of immunologically active and potentially deleterious EVs from PCa cells and local immune cell populations that can contribute to oxidative stress and inflammatory response induction in local and distant cell populations including neutrophils, T cells, and urothelial cells, potentially driving a feedback loop exacerbating RT-associated tissue damage. Source of Funding: University of Rochester Medical Center Departmental Funding © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e146 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryan Molony More articles by this author Sarah Kerns More articles by this author Brian Marples More articles by this author Emmanuel Oshodi More articles by this author YuhChyau Chen More articles by this author Yi-Fen Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Variability in the Response against Teladorsagia circumcincta in Lambs of Two Canarian Sheep Breeds

The increasing resistance to anthelmintics has necessitated the exploration of alternative control strategies of gastrointestinal nematode (GIN) infections. A sustainable option is genetic selection based on differences in susceptibility to GIN infection between and within breeds of sheep. Here, three-month-old Canaria Hair breed (GIN-resistant) and Canaria Sheep breed (GIN-susceptible) showed no significant between-breed differences after trickle infection with Teladorsagia circumcincta, whereas considerable individual variability was found in both breeds. Next, data from lambs of both breeds were used to explore the relationships between parasitological variables and T. circumcincta-specific IgA levels, local immune cell populations, and abomasal lymph node gene expression to understand the possible mechanisms underlying resistance. Mucosal IgA levels as well as numbers of globular leukocytes and MHC-II+ cells were associated with protection. Analysis of lymph node gene expression revealed the associations between lower parasite numbers and cumulative fecal egg counts and several immune pathways, such as leukocyte cell adhesion, activation and differentiation of T cells, in particular CD4+ and IL-4 production. The data obtained here may inform on the relationship between phenotypic resistance variability and protective responses at the humoral, cellular, and transcriptomic levels, thus contributing to identifying immune responses in young lambs that could be used as markers for selection.

Decidual natural killer cells and trophoblast cells: cellular, humoral and molecular mechanisms of interaction

Natural killer cells (NK cells) represent a group of lymphocytes of innate immunity. In addition to NK cells of peripheral blood, tissue-resident populations are described. NK cells of the decidual envelope (decidual NK cells) represent one of the local NK cell populations. Decidual NK cells differ in phenotype and function from peripheral blood NK cells. These cells have, mainly, regulatory functions. At the same time they retain the ability to perform cytotoxic effects. In the uterus, NK cells are located closely to the cells of fetal origin, i.e., trophoblast cells, which differentiate from the outer layer of the invading blastocyst. The purpose of the review article was to analyze the literature data on the studies of the molecular interactions between NK cells and trophoblast cells, as well as potential means of regulating these interactions. The review presents currently available data on receptor-mediated effects (due to adhesion molecules and cytotoxic receptors) and distant interactions (involving cytokines, chemokines and growth factors secreted by the both cell types) between NK population and trophoblast cells. The receptors regulating contacts of NK cells and trophoblast cells with extracellular matrix are also considered. The review provides information on activation of signaling pathways in NK cells and trophoblast cells resulting from their interaction with each other and components of the extracellular matrix. Currently, the molecular mechanisms regulating the NK cell functions and their interaction with trophoblast cells have not been studied sufficiently. The authors attempted to consider molecular regulation of the functional activity of NK cells mediated by the molecular complex of RNA polymerase II. We also describe participation of cyclin-dependent CDK8/19 kinases which comprise a part of the mediator complex which provides functioning of immune cells. The data on the participation of CDK8/19 in regulation of intracellular signaling pathways, as well as influence of CDK8/19 on the NK cell functions, are considered. Summarizing the data presented in the literature, one may emphasize that there is an extensive mutual influence of NK cells and trophoblast cells in decidual lining of uterus during pregnancy, thus leading to a changes in phenotype and functions of these cells. Experimental studies are required on the contribution of molecular mechanisms involved in transcription and translation processes to the biology of NK cells, and their role in maintaining interactions between NK cells and trophoblast cells, including the pathways involving CDK8/19.

Social regulation of immediate early gene induction in gonadotropin releasing-hormone 1 neurons and singing behavior in canaries (Serinus canaria)

Social cues modulate the neuroendocrine control of reproduction. However, the neural systems involved in the integration of social cues are not well described. Gonadotropin-releasing hormone 1 (GnRH1) cells in the preoptic area (POA) are the final common node that links the brain with peripheral reproductive physiology. These experiments investigated whether induction of the immediate early gene, EGR1, in anatomically localized GnRH1 cell populations in Border canaries is regulated by the social environment. First, we characterized behavioral modifications in singing behavior and found males paired with a female for 2 weeks significantly reduced many aspects of singing behavior. However, paired males had a significantly higher percentage of GnRH1 cells co-labeled with EGR1. The second experiment manipulated the social environment by pairing males and females in mixed sex dyads, same sex dyads or housed birds in isolation. Only when birds are paired in mixed sex dyads was there a significantly greater percentage of GnRH1 cells expressing EGR1 cells. Increased GnRH1-EGR1 co-expression was localized to the rostral POA. These data reveal that discrete GnRH1 cells are involved in the neural integration of specific social cues and support the hypothesis that the POA exhibits functional topography related to courtship and sexual behaviors.

Tongue immune compartment analysis reveals spatial macrophage heterogeneity.

The tongue is a unique muscular organ situated in the oral cavity where it is involved in taste sensation, mastication, and articulation. As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches. Cx3cr1+ macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae. Folr2+ macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders.

Mapping the epithelial\u2013immune cell interactome upon infection in the gut and the upper airways

Increasing evidence points towards the key role of the epithelium in the systemic and over-activated immune response to viral infection, including SARS-CoV-2 infection. Yet, how viral infection alters epithelial–immune cell interactions regulating inflammatory responses, is not well known. Available experimental approaches are insufficient to properly analyse this complex system, and computational predictions and targeted data integration are needed as an alternative approach. In this work, we propose an integrated computational biology framework that models how infection alters intracellular signalling of epithelial cells and how this change impacts the systemic immune response through modified interactions between epithelial cells and local immune cell populations. As a proof-of-concept, we focused on the role of intestinal and upper-airway epithelial infection. To characterise the modified epithelial–immune interactome, we integrated intra- and intercellular networks with single-cell RNA-seq data from SARS-CoV-2 infected human ileal and colonic organoids as well as from infected airway ciliated epithelial cells. This integrated methodology has proven useful to point out specific epithelial–immune interactions driving inflammation during disease response, and propose relevant molecular targets to guide focused experimental analysis.

On vasa vasorum: A history of advances in understanding the vessels of vessels.

The vasa vasorum are a vital microvascular network supporting the outer wall of larger blood vessels. Although these dynamic microvessels have been studied for centuries, the importance and impact of their functions in vascular health and disease are not yet fully realized. There is now rich knowledge regarding what local progenitor cell populations comprise and cohabitate with the vasa vasorum and how they might contribute to physiological and pathological changes in the network or its expansion via angiogenesis or vasculogenesis. Evidence of whether vasa vasorum remodeling incites or governs disease progression or is a consequence of cardiovascular pathologies remains limited. Recent advances in vasa vasorum imaging for understanding cardiovascular disease severity and pathophysiology open the door for theranostic opportunities. Approaches that strive to control angiogenesis and vasculogenesis potentiate mitigation of vasa vasorum–mediated contributions to cardiovascular diseases and emerging diseases involving the microcirculation.

T cell fat catabolism: A novel target for kynurenine?

T cell fat catabolism: A novel target for kynurenine?

Immune cell profile and immune-related gene expression of obese peripheral blood and liver tissue.

Obesity is associated with changes in immune cell subpopulations. However, tissue and blood obesity-responsive immune phenotypic pathways have not been contrasted. Here, the local niche immune cell population and gene expression in fatty liver is compared to peripheral blood of obese individuals. The Cibersort algorithm enumerated increased fractions of memory CD4+ T lymphocytes and reductions in natural killer and memory B cells in obese liver tissue and obese blood, with similar reductions found in nonalcoholic fatty liver disease tissue. Gene expression analysis identified inflammatory immune signatures of regulatory CD4+ T cells with inferred Th1, Th17, Th2, or Treg phenotypes that differed between liver and blood. Our study suggests that the local tissue-specific immune phenotype in the liver differs from the obese peripheral circulation, with the latter reflective of multisystemic persistent inflammation that is characteristic of obesity.

Therapeutic potential of pro-resolving mediators in diabetic kidney disease.

Renal microvascular disease associated with diabetes [Diabetic kidney disease - DKD] is the leading cause of chronic kidney disease. In DKD, glomerular basement membrane thickening, mesangial expansion, endothelial dysfunction, podocyte cell loss and renal tubule injury contribute to progressive glomerulosclerosis and tubulointerstitial fibrosis. Chronic inflammation is recognized as a major pathogenic mechanism for DKD, with resident and circulating immune cells interacting with local kidney cell populations to provoke an inflammatory response. The onset of inflammation is driven by the release of well described proinflammatory mediators, and this is typically followed by a resolution phase. Inflammation resolution is achieved through the bioactions of endogenous specialized pro-resolving lipid mediators (SPMs). As our understanding of SPMs advances 'resolution pharmacology' based approaches using these molecules are being explored in DKD.

Involvement of Kynurenine Pathway in Hepatocellular Carcinoma.

Simple SummaryThe kynurenine pathway (KP) is a biochemical pathway that synthesizes the vital coenzyme, nicotinamide adenine dinucleotide (NAD+). In cancer, the KP is significantly activated, leading to tryptophan depletion and the production of downstream metabolites, which skews the immune response towards tumour tolerance. More specifically, advanced stage cancers that readily metastasize evidence the most dysregulation in KP enzymes, providing a clear link between the KP and cancer morbidity. Consequently, this provides the rationale for an attractive new drug discovery opportunity for adjuvant therapeutics targeting KP-mediated immune tolerance, which would greatly complement current pharmacological interventions. In this review, we summarize recent developments in the roles of the KP and clinical trials examining KP inhibition in liver cancer.As the second and third leading cancer-related death in men and the world, respectively, primary liver cancer remains a major concern to human health. Despite advances in diagnostic technology, patients with primary liver cancer are often diagnosed at an advanced stage. Treatment options for patients with advanced hepatocarcinoma (HCC) are limited to systemic treatment with multikinase inhibitors and immunotherapy. Furthermore, the 5-year survival rate for these late-stage HCC patients is approximately 12% worldwide. There is an unmet need to identify novel treatment options and/or sensitive blood-based biomarker(s) to detect this cancer at an early stage. Given that the liver harbours the largest proportion of immune cells in the human body, understanding the tumour–immune microenvironment has gained increasing attention as a potential target to treat cancer. The kynurenine pathway (KP) has been proposed to be one of the key mechanisms used by the tumour cells to escape immune surveillance for proliferation and metastasis. In an inflammatory environment such as cancer, the KP is elevated, suppressing local immune cell populations and enhancing tumour growth. In this review, we collectively describe the roles of the KP in cancer and provide information on the latest research into the KP in primary liver cancer.

Acute-phase protein synthesis: a key feature of innate immune functions of the liver.

The expression of acute-phase proteins (APP's) maintains homeostasis and tissue repair, but also represents a central component of the organism's defense strategy, especially in the context of innate immunity. Accordingly, an inflammatory response is accompanied by significant changes in the serum protein composition, an aspect that is also used diagnostically. As the main site of APP synthesis the liver is constantly exposed to antigens or pathogens via blood flow, but also to systemic inflammatory signals originating either from the splanchnic area or from the circulation. Under both homeostatic and acute-phase response (APR) conditions the composition of APP's is determined by the pattern of regulatory mediators derived from the systemic circulation or from local cell populations, especially liver macrophages. The key regulators mentioned here most frequently are IL-1β, IL-6 and TNF-α. In addition to a variety of molecular mediators described mainly on the basis of in vitro studies, recent data emphasize the in vivo relevance of cellular key effectors as well as molecular key mediators and protein modifications for the regulation and function of APP's. These are aspects, on which the present review is primarily focused.