Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other ...macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.
Circadian clocks allow the temporal compartmentalization of biological processes. In Arabidopsis, circadian rhythms display organ specificity but the underlying molecular causes have not been ...identified. We investigated the mechanisms responsible for the similarities and differences between the clocks of mature shoots and roots in constant conditions and in light : dark cycles.
We developed an imaging system to monitor clock gene expression in shoots and light- or dark-grown roots, modified a recent mathematical model of the Arabidopsis clock and used this to simulate our new data.
We showed that the shoot and root circadian clocks have different rhythmic properties (period and amplitude) and respond differently to light quality. The root clock was entrained by direct exposure to low-intensity light, even in antiphase to the illumination of shoots. Differences between the clocks were more pronounced in conditions where light was present than in constant darkness, and persisted in the presence of sucrose. We simulated the data successfully by modifying those parameters of a clock model that are related to light inputs.
We conclude that differences and similarities between the shoot and root clocks can largely be explained by organ-specific light inputs. This provides mechanistic insight into the developing field of organ-specific clocks.
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease ...associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing TRM ...cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish "antigen-specific" from "bystander" reactivation, we demonstrate that lung CD8+ TRM cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (TLN cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8+ TLN cells, which is strictly dependent on CD11c+XCR1+ APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8+ TRM cells, but the quality of TRM cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.
Regulatory T cells (T
cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue T
cells. We found that ...epigenetic modifications defined the molecular characteristics of tissue T
cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue T
cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue T
cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the T
2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue T
cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.
Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through ...activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
► The gut microbiota reduces bile acid pool size and composition ► The gut microbiota activates FXR by alleviating receptor antagonism ► Tauro-conjugated muricholic acids are naturally occurring FXR antagonists
The identification of stem cells and growth factors as well as the development of biomaterials hold great promise for regenerative medicine applications. However, the therapeutic efficacy of ...regenerative therapies can be greatly influenced by the host immune system, which plays a pivotal role during tissue repair and regeneration. Therefore, understanding how the immune system modulates tissue healing is critical to design efficient regenerative strategies. While the innate immune system is well known to be involved in the tissue healing process, the adaptive immune system has recently emerged as a key player. T-cells, in particular, regulatory T-cells (Treg), have been shown to promote repair and regeneration of various organ systems. In this review, we discuss the mechanisms by which Treg participate in the repair and regeneration of skeletal and heart muscle, skin, lung, bone, and the central nervous system.
Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to ...profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.
•In contrast to mice, human ILCs are less strictly compartmentalized•ILC subset composition is differentially impacted by tissue localization•Tissue environment drives transcriptional heterogeneity in a subset-dependent way•ILC1 exhibit greater transcriptional heterogeneity in mucosal versus lymphoid sites
Innate lymphoid cells (ILC) critically regulate tissue immunity and homeostasis in mice, but limited access to healthy human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Yudanin and colleagues provide a comprehensive map of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.
In recent years, attention has turned to examining the biodistribution of EVs in recipient animals to bridge between knowledge of EV function in vitro and in vivo. We undertook a systematic review of ...the literature to summarize the biodistribution of EVs following administration into animals. There were time‐dependent changes in the biodistribution of small‐EVs which were most abundant in the liver. Detection peaked in the liver and kidney in the first hour after administration, while distribution to the lungs and spleen peaked between 2–12 h. Large‐EVs were most abundant in the lungs with localization peaking in the first hour following administration and decreased between 2–12 h. In contrast, large‐EV localization to the liver increased as the levels in the lungs decreased. There was moderate to low localization of large‐EVs to the kidneys while localization to the spleen was typically low. Regardless of the origin or size of the EVs or the recipient species into which the EVs were administered, the biodistribution of the EVs was largely to the liver, lungs, kidneys, and spleen. There was extreme variability in the methodology between studies and we recommend that guidelines should be developed to promote standardization where possible of future EV biodistribution studies.
Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in ...vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNɣ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.
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•Gene expression profiling mapped systemic macrophage responses to sepsis, MI, and stroke•The tissue microenvironment determined phenotypic adaptions following remote injury•Local proliferation dominated over recruitment in expanding tissue macrophage numbers•Alveolar macrophage priming post MI increased resilience against subsequent pneumonia
Hoyer, Naxerova, et al. generate a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. They find that local injury activates macrophages in remote organs and that these adaptations were damaging or protective in different settings.
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