-
Frontiers in Immunology 2020Paneth cells contribute to intestinal innate immunity by sensing bacteria and secreting α-defensin. In Institute of Cancer Research (ICR) mice, α-defensin termed...
Paneth cells contribute to intestinal innate immunity by sensing bacteria and secreting α-defensin. In Institute of Cancer Research (ICR) mice, α-defensin termed cryptdin (Crp) in Paneth cells consists of six major isoforms, Crp1 to 6. Despite accumulating evidences that α-defensin functions in controlling the intestinal microbiota, topographical localization of Paneth cells in the small intestine in relation to functions of α-defensin remains to be determined. In this study, we examined the expression level of messenger RNA (mRNA) encoding six Crp-isoforms and Crp immunoreactivities using singly isolated crypts together with bactericidal activities of Paneth cell secretions from isolated crypts of duodenum, jejunum, and ileum. Here we showed that levels of Crp mRNAs in the single crypt ranged from 5 x 10 to 1 x 10 copies per 5 ng RNA. For each Crp isoform, the expression level in ileum was 4 to 50 times higher than that in duodenum and jejunum. Furthermore, immunohistochemical analysis of isolated crypts revealed that the average number of Paneth cell per crypt in the small intestine increased from proximal to distal, three to seven-fold, respectively. Both Crp1 and 4 expressed greater in ileal Paneth cells than those in duodenum or jejunum. Bactericidal activities in secretions of ileal Paneth cell exposed to bacteria were significantly higher than those of duodenum or jejunum. In germ-free mice, Crp expression in each site of the small intestine was attenuated and bactericidal activities released by ileal Paneth cells were decreased compared to those in conventional mice. Taken together, Paneth cells and their α-defensin in adult mouse appeared to be regulated topographically in innate immunity to control intestinal integrity.
Topics: Animals; Anti-Infective Agents; Cells, Cultured; Gene Expression Regulation; Immunity, Innate; Intestine, Small; Male; Mice; Mice, Inbred ICR; Paneth Cells; Protein Precursors; Protein Transport; RNA, Messenger; alpha-Defensins
PubMed: 33154750
DOI: 10.3389/fimmu.2020.570296 -
Science Advances Nov 2023The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the...
The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the niche microenvironment providing various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. Different Wnt ligands can selectively activate β-catenin-dependent (canonical) or -independent (noncanonical) signaling. Here, we report that the Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and noncanonical Wnt (Wnt/PCP) signaling. Daam1/2 interacts with the Wnt inhibitor RNF43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing RNF43-dependent degradation of the Wnt receptor, Frizzled (Fzd). Single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion because of defective Wnt/PCP signaling. Together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and noncanonical Wnt, which is fundamental for specifying an adequate number of Paneth cells.
Topics: Animals; Wnt Signaling Pathway; Paneth Cells; Intestines; Cell Differentiation; Stem Cells; Mammals
PubMed: 38000028
DOI: 10.1126/sciadv.adh9673 -
The EMBO Journal Nov 2023Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and...
Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74 PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74 PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.
Topics: Humans; Animals; Mice; Paneth Cells; Intestine, Small; Inflammation; Microbiota; Cytokines
PubMed: 37718683
DOI: 10.15252/embj.2023113975 -
Histopathology Feb 2021Owing to a sharp increase in the frequency of diagnosis of colorectal adenomas in the current era of population screening, distinctive morphological features are... (Review)
Review
Owing to a sharp increase in the frequency of diagnosis of colorectal adenomas in the current era of population screening, distinctive morphological features are increasingly being observed. These may present diagnostic challenges and cause clinical management issues. Paneth cell metaplasia is a more common occurrence, but the incidence rates of squamous metaplasia, clear cell metaplasia, osseous metaplasia, neuroendocrine differentiation and signet-ring cell-like lesion are low, and they can be seen in <1% of colorectal adenomas. Their histomorphological characteristics are quite unique; ancillary studies are not very helpful and often not needed. In this review, we give an overview and describe the potential clinical consequences of such incidental and special morphological findings in colorectal adenomas.
Topics: Adenoma; Colorectal Neoplasms; Humans; Incidence; Metaplasia; Neuroendocrine Cells; Ossification, Heterotopic; Paneth Cells
PubMed: 32981102
DOI: 10.1111/his.14263 -
Current Biology : CB Jun 2021Apoptotic cells are quickly and efficiently engulfed and removed via the process of efferocytosis by either professional phagocytes, such as macrophages, or...
Apoptotic cells are quickly and efficiently engulfed and removed via the process of efferocytosis by either professional phagocytes, such as macrophages, or non-professional phagocytes, including epithelial cells. In addition to debris removal, a key benefit of efferocytosis is that phagocytes engulfing apoptotic cells release anti-inflammatory mediators that help reduce local tissue inflammation; conversely, accumulation of uncleared apoptotic cells predisposes to a pro-inflammatory tissue milieu. Due to their high proliferative capacity, intestinal epithelial cells (iECs) are sensitive to inflammation, irradiation, and chemotherapy-induced DNA damage, leading to apoptosis. Mechanisms of iEC death in the context of irradiation has been studied, but phagocytosis of dying iECs is poorly understood. Here, we identify an unexpected efferocytic role for Paneth cells, which reside in intestinal crypts and are linked to innate immunity and maintenance of the stem cell niche in the crypt. Through a series of studies spanning in vitro efferocytosis, ex vivo intestinal organoids ("enteroids"), and in vivo Cre-mediated deletion of Paneth cells, we show that Paneth cells mediate apoptotic cell uptake of dying neighbors. The relevance of Paneth-cell-mediated efferocytosis was revealed ex vivo and in mice after low-dose cesium-137 (Cs) irradiation, mimicking radiation therapies given to cancer patients often causing significant apoptosis of iECs. These data advance a new concept that Paneth cells can act as phagocytes and identify another way in which Paneth cells contribute to the overall health of the intestine. These observations also have implications for individuals undergoing chemotherapy or chronic inflammatory bowel disease.
Topics: Animals; Apoptosis; Humans; Inflammation; Intestines; Mice; Paneth Cells; Phagocytes; Phagocytosis
PubMed: 33852873
DOI: 10.1016/j.cub.2021.03.055 -
Canadian Journal of Gastroenterology =... Dec 2011Autophagy is a conserved cellular pathway that maintains intracellular homeostasis by degrading proteins and cytosolic contents of eukaryotic cells. Autophagy clears... (Review)
Review
Autophagy is a conserved cellular pathway that maintains intracellular homeostasis by degrading proteins and cytosolic contents of eukaryotic cells. Autophagy clears misfolded and long-lived proteins, damaged organelles and invading microorganisms from cells, and provides nutrients and energy in response to exposure to cell stressors such as starvation. Defective autophagy has recently been linked to a diverse range of disease processes of relevance to gastroenterologists and hepatologists including Crohn's disease, pancreatitis, hepatitis and cancer. The present article provides an overview of the autophagy pathway and discusses gastrointestinal disease processes in which alterations in autophagy have been implicated. The clinical significance of autophagy as a potential therapeutic option is also discussed.
Topics: Acute Disease; Autophagy; Crohn Disease; Cystic Fibrosis; Gastroenterology; Gastrointestinal Diseases; Humans; Pancreatitis; Paneth Cells; Proteostasis Deficiencies; Reperfusion Injury; TOR Serine-Threonine Kinases
PubMed: 22175057
DOI: 10.1155/2011/581264 -
Nature Communications Dec 2023Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is...
Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract is not well known. Here, we describe the development of PCM in a murine model of chronic myelogenous leukemia (CML) that is driven by an inducible bcr-abl oncogene. Mechanistically, CML induces a proinflammatory state within the GI tract that results in the production of epithelial-derived IL-33. The binding of IL-33 to the decoy receptor ST2 leads to IL-9 production by type 2 innate lymphoid cells (ILC2) which is directly responsible for the induction of PCM in the colon and tissue remodeling in the small intestines, characterized by goblet and tuft cell hyperplasia along with expansion of mucosal mast cells. Thus, we demonstrate that an extra-intestinal disease can trigger an ILC2/IL-9 immune circuit, which induces PCM and regulates epithelial cell fate decisions in the GI tract.
Topics: Animals; Mice; Paneth Cells; Interleukin-9; Immunity, Innate; Interleukin-33; Lymphocytes; Intestine, Small; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metaplasia
PubMed: 38042840
DOI: 10.1038/s41467-023-43248-5 -
Biology of Blood and Marrow... Jan 2016Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights... (Review)
Review
Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell-signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits.
Topics: Acute Disease; Allografts; Cytokines; Gastrointestinal Microbiome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Intestinal Diseases; Paneth Cells; Signal Transduction; Stomach Diseases; T-Lymphocytes
PubMed: 26453971
DOI: 10.1016/j.bbmt.2015.10.001 -
Trends in Parasitology Feb 2021The protozoan parasite Entamoeba histolytica is the causative agent of amebiasis, an infection that manifests as colitis and, in some cases, liver abscess. A better... (Review)
Review
The protozoan parasite Entamoeba histolytica is the causative agent of amebiasis, an infection that manifests as colitis and, in some cases, liver abscess. A better understanding of host protective factors is key to developing an effective remedy. Recently, significant advances have been made in understanding the mechanisms of MUC2 production by goblet cells upon amebic infection, regulation of antimicrobial peptide production by Paneth cells, the interaction of commensal microbiota with immune stimulation, and host genetics in conferring protection from amebiasis. In addition to host pathways that may serve as potential therapeutic targets, significant progress has also been made with respect to development of a vaccine against amebiasis. Here, we aim to highlight the current understanding and knowledge gaps critically.
Topics: Entamoeba histolytica; Entamoebiasis; Goblet Cells; Host-Parasite Interactions; Humans; Mucin-2; Paneth Cells; Pore Forming Cytotoxic Proteins; Protozoan Vaccines
PubMed: 33502317
DOI: 10.1016/j.pt.2020.09.015 -
Gastroenterology Feb 2011
Topics: Animals; Endoplasmic Reticulum; Humans; Inflammatory Bowel Diseases; Intestine, Small; Mice; Paneth Cells; Rats; Reperfusion Injury; Stress, Physiological; Unfolded Protein Response
PubMed: 21172333
DOI: 10.1053/j.gastro.2010.12.015