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The Journal of Clinical Investigation Aug 2023Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential...
Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through localized interactions primed EC responses to form ICAM-1 "hot spots" to support PMN TEM. Using real-time intravital microscopy of LPS-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM, and subsequent accumulation in the intestinal mucosa. Anti-colony stimulating factor 1 receptor Ab-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNF-α-KO macrophage chimeras, TNF-α/TNF receptor (TNF-α/TNFR) neutralization, and multicellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNF-α and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanisms by which macrophages regulate PMN trafficking in inflamed mucosa.
Topics: Humans; Mice; Animals; Endothelial Cells; Intercellular Adhesion Molecule-1; Tumor Necrosis Factor-alpha; Cell Adhesion; Neutrophil Infiltration; Cells, Cultured; Intestinal Mucosa; Neutrophils; Macrophages; Endothelium, Vascular
PubMed: 37261911
DOI: 10.1172/JCI170733 -
Nature Apr 2024The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens....
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T) cell development and function have been identified, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T (eT) cell function. eT cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103SIRPα dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 macrophages and eT cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Topics: Animals; Female; Male; Mice; Antigens, CD; Dendritic Cells; Gene Expression Profiling; Helicobacter hepaticus; Helicobacter Infections; Immune Tolerance; Inflammation; Integrin alpha Chains; Intestinal Mucosa; Macrophages; Mice, Inbred C57BL; Mucous Membrane; Receptors, Immunologic; Single-Cell Gene Expression Analysis; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 38570678
DOI: 10.1038/s41586-024-07251-0 -
Internal and Emergency Medicine Mar 2024The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition... (Review)
Review
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
Topics: Humans; Autoimmune Diseases; Gastrointestinal Microbiome; Inflammation; Intestinal Barrier Function; Intestinal Mucosa; Non-alcoholic Fatty Liver Disease
PubMed: 37505311
DOI: 10.1007/s11739-023-03374-w -
The Journal of Experimental Medicine Oct 2023Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA...
Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue-type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify seven MC subsets (MC1-7) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the bladder, MC2 in the lungs, and MC4, MC6, and MC7 in the skin. Conversely, MC3 and MC5 are shared by most organs but not skin. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.
Topics: Humans; Mice; Animals; Mast Cells; Mucous Membrane; Transcriptome
PubMed: 37462672
DOI: 10.1084/jem.20230570 -
Nature Immunology Sep 2023Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the...
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4 T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4 T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4 T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
Topics: Humans; Mice; Animals; Mucous Membrane; Salmonella typhimurium; T-Lymphocytes; Immunity, Mucosal
PubMed: 37580603
DOI: 10.1038/s41590-023-01587-x -
Revista Espanola de Enfermedades... Oct 2023Esophageal tuberculosis (ET) is an extremely rare disease and herein, we present an ET case. Endoscopic findings of ET are variable and diverse and can be easily...
Esophageal tuberculosis (ET) is an extremely rare disease and herein, we present an ET case. Endoscopic findings of ET are variable and diverse and can be easily mistaken for malignancy. A definitive diagnosis of ET is difficult to make with white light endoscopy alone, and the diagnostic yield of a biopsy is low in secondary ET cases with normal overlying mucosa. Although the findings of conventional endoscopy and endoscopic ultrasonography in ET have been reported so far, few reports have described the findings of magnifying endoscopy with narrow-band imaging (ME-NBI). Dilated microvessels without irregularities on ME-NBI may be useful to differentiate secondary ET from esophageal carcinoma, since the findings suggest compression from the depth. Although rare, ET has to be considered in the differential diagnosis for any unexplained esophageal lesions.
Topics: Humans; Esophagoscopy; Esophageal Neoplasms; Mucous Membrane; Biopsy; Narrow Band Imaging
PubMed: 36043542
DOI: 10.17235/reed.2022.9108/2022