The term ‘macrophage’ encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. ...CSF1/IL‐34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue‐specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue‐resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell‐intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life‐history versus environment in macrophage programming and function.
Macrophage function depends upon survival, transcriptional identity, and epigenetic status, which are products of both environmental and cell‐intrinsic factors. Thus, the view of macrophages as wholly plastic cells must be reconsidered. This review raises unanswered questions about the relative importance of cell life‐history versus environment in macrophage programming and function.
Abstract
Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by
tumor protein p63 (TP63)
, a ...master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify
sterol regulatory element binding transcription factor 1 (SREBF1)
as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/
Kruppel like factor 5 (KLF5)
is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.
Livers from controlled donation after circulatory death (DCD) donors suffer a higher incidence of nonfunction, poor function, and ischemic cholangiopathy. In situ normothermic regional perfusion ...(NRP) restores a blood supply to the abdominal organs after death using an extracorporeal circulation for a limited period before organ recovery. We undertook a retrospective analysis to evaluate whether NRP was associated with improved outcomes of livers from DCD donors. NRP was performed on 70 DCD donors from whom 43 livers were transplanted. These were compared with 187 non-NRP DCD donor livers transplanted at the same two UK centers in the same period. The use of NRP was associated with a reduction in early allograft dysfunction (12% for NRP vs. 32% for non-NRP livers, P = .0076), 30-day graft loss (2% NRP livers vs. 12% non-NRP livers, P = .0559), freedom from ischemic cholangiopathy (0% vs. 27% for non-NRP livers, P < .0001), and fewer anastomotic strictures (7% vs. 27% non-NRP, P = .0041). After adjusting for other factors in a multivariable analysis, NRP remained significantly associated with freedom from ischemic cholangiopathy (P < .0001). These data suggest that NRP during organ recovery from DCD donors leads to superior liver outcomes compared to conventional organ recovery.
In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors ...powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.
Tissue-resident macrophages Davies, Luke C; Jenkins, Stephen J; Allen, Judith E ...
Nature immunology,
10/2013, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as ...clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo.
How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients ...hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8
or CD4
T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid ...culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.
Macrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the ...proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling. However, both IL-4Rα-dependent and -independent mechanisms contributed to MΦ proliferation during nematode infections. IL-4R-independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4Rα expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4Rα(+) compared with IL-4Rα(-) cells. Mechanistically, this occurred by conversion of IL-4Rα(+) MΦs from a CSF-1-dependent to -independent program of proliferation. Thus, IL-4 increases the relative density of tissue MΦs by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4Rα signaling triggered proliferation above homeostatic levels, only CSF-1 led to the recruitment of monocytes and neutrophils. Thus, the IL-4 pathway of proliferation may have developed as an alternative to CSF-1 to increase resident MΦ numbers without coincident monocyte recruitment.
Background
Probiotics may be effective in reducing the duration of acute infectious diarrhoea.
Objectives
To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.
Search ...methods
We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review.
Selection criteria
Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent.
Data collection and analysis
Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events.
Main results
We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster‐randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high.
Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta‐analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes.
In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate‐certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low‐certainty evidence).
Effect size was similar and marked heterogeneity persisted in pre‐specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered.
For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD ‐18.03 hours, 95% CI ‐27.28 to ‐8.78, random‐effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants).
No serious adverse events were attributed to probiotics.
Authors' conclusions
Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.
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