The gastrointestinal (GI) tract represents a unique challenge to the mammalian immune system. It must tolerate the presence of the luminal microbiota and thus not respond to their products, but still ...protect the intestinal mucosa from potentially harmful dietary antigens and invading pathogens. The intestinal epithelium, composed of a single layer of cells, is crucial for preserving gut homeostasis and acts both as a physical barrier and as a coordinating hub for immune defense and crosstalk between bacteria and immune cells. We highlight here recent findings regarding communication between microbes and intestinal epithelial cells (IECs), as well as the immune mechanisms employed by distinct IEC subsets to promote homeostasis, emphasizing the central and active role that these cells play in host enteric defense.
The intestinal epithelium is an integral component of innate immunity, defending the host by actively responding through various mechanisms that protect the mucosal barrier.
IECs provide the first line of defense against noxious luminal stimuli, and professional immune cells are only activated once these defenses are overcome.
The epithelium primes and signals professional immune cells to promote an effective inflammatory/immune response.
The makeup of the intestinal epithelium is diverse and consists of multiple cell types (i.e., enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), and these can develop further into specialized subsets.
Through their diverse functions, these different epithelial cell types work in concert to maintain intestinal homeostasis and promote host defense.
The cross-talk between mesenchymal stem and stromal cells (MSCs) and macrophages is critical for the restoration of tissue homeostasis after injury. Here, we demonstrate a pathway through which MSCs ...instruct macrophages to resolve inflammation and preserve tissue-specific stem cells, leading to homeostasis in mice with autoimmune uveoretinitis and sterile-injury-induced corneal epithelial stem cell deficiency. Distinct from their conventional role in macrophage reprogramming to anti-inflammatory phenotype by a PGE2-dependent mechanism, MSCs enhance the phagocytic activity of macrophages, which partly depends on the uptake of MSC mitochondria-containing extracellular vesicles. The MSC-primed macrophages increase the secretion of amphiregulin (AREG) in a phagocytosis-dependent manner. AREG is essential for MSC-primed macrophages to suppress immune responses through regulatory T (Treg) cells and to protect corneal epithelial stem cells via apoptosis inhibition and proliferation promotion. Hence, the data reveal that MSCs harness macrophage-derived AREG to maintain tissue homeostasis after injury and provide a therapeutic target in immune-mediated disease and regenerative medicine.
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•MSCs enhance macrophage phagocytosis through MSC mitochondria-containing vesicles•MSCs elicit secretion and transcription of amphiregulin in macrophages•Amphiregulin secretion depends on macrophage phagocytosis and MSC vesicle uptake•Macrophage amphiregulin increases Treg cells and preserves epithelial stem cells
Ko et al. demonstrate that amphiregulin (AREG) is an important growth factor that mediates the cross-talk between immune cells and epithelial cells for inflammation resolution and tissue regeneration, leading to homeostasis after injury. Mesenchymal stem and stromal cells (MSCs) activate this cross-talk by inducing transcription and secretion of AREG in macrophages.
Liver cirrhosis is characterized by the extensive deposition of extracellular matrix such as fibril collagen, causing dysfunction and failure of the liver. Hepatic macrophages play pivotal roles in ...the transition from inflammatory to restorative properties upon hepatic injury. In particular, scar‐associated macrophages (SAMacs) control liver fibrosis with the representative expression of matrix metalloproteinase (MMP). However, the heterogenic SAMac population has not been well characterized yet. This study profiled heterogeneous liver macrophages using public databases of single‐cell transcriptomics and found T‐cell immunoglobulin and mucin containing (TIM)4− macrophages exhibited elevated expression of MMPs. Scar‐associated triggering receptor expressed on myeloid cells (TREM)2 was positively correlated with MMP expression, suggesting that TREM2+ subsets exert their fibrotic role via MMPs. During the progression of diet‐induced nonalcoholic steatohepatitis and drug‐induced liver cirrhosis, monocyte‐derived TREM2+ macrophages accumulate in the liver with the distinct expression of MMPs. A noticeable expansion of MMP‐ and TREM2‐ double positive macrophages was observed in fibrotic scar regions. Consistently, the analysis of single‐cell transcriptomics for human cirrhotic livers supported the theory that TREM2+ SAMacs are strongly associated with MMPs. The results could expand the understanding of liver fibrosis and SAMac, offering potential therapeutic approaches for liver cirrhosis.
In this work, we found that TREM2+ macrophages within the TIM4‐ macrophage population markedly express matrix metalloproteinase (MMP) 12, 13 and 14 to modulate the progression of hepatic fibrosis. The expression of MMPs and TREM2 are positively correlated in liver macrophages. TREM2+ macrophages closely localize to the fibrotic area and control hepatic scar formation via the production of abundant MMPs.
AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor ...immunity, particularly the function of regulatory T cells (Tregs), is poorly defined.
AMPKα1
Foxp3
, Foxp3
, Rag1
, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation.
The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3β (GSK-3β), inhibiting the expression of PD-1 in Tregs.
Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3β signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.
Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests ...that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α–stimulated gene/protein (TSG)-6–dependent manner. As a result, mice were protected against subsequent immune challenge in two models of alloand autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell–suppressive activities independently of FoxP3⁺ regulatory T cells. Adoptive transfer of MSC-induced B220⁺CD11b⁺ monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II⁺B220⁺CD11b⁺ cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages.
The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk ...allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.
Lentinan extracted from shiitake (Lentinula edodes) is a β-glucan that has been reported as an intravenous anti-tumor polysaccharide via enhancement of the host immune system. In this study, we ...determined the effect of lentinan on inflammasome activation, a multi-protein platform, in myeloid cells. Mouse bone marrow-derived macrophages were treated with lentinan with/without inflammasome triggers, and maturation of interleukin (IL)-1β, IL-18, or caspase-1 was measured as a readout of inflammasome activation. As a result, lentinan selectively inhibited absent in melanoma 2 (AIM2) inflammasome activation. In addition, lentinan up-regulated pro-inflammatory cytokines and induced expression of inflammasome-related genes through toll-like receptor 4 signaling. Furthermore, we assessed the effect of lentinan on mice treated with Listeria monocytogenes or lipopolysaccharide as an AIM2 or non-canonical inflammasome-mediated model. Lentinan attenuated IL-1β secretion resulting from Listeria-mediated AIM2 inflammasome activation and reduced endotoxin lethality via inhibition of non-canonical inflammasome activation. Thus, lentinan is suggested as an anti-AIM2 and anti-non-canonical inflammasome candidate despite its up-regulation of cytokine expression.
•We performed the extended receiver operating characteristic (ROC) analysis which included calculating the volume under the ROC surface (VUS) and the Youden index to determine multi-category ...discriminatory ability of the 15-item short form of the GDS (GDS-15).•The GDS-15 was useful tool for multi-category classification of geriatric depression as normal, minor depressive disorder (MnDD), and major depressive disorder (MDD).•Based on the Youden index, we suggest the cutoff points between normal and MnDD as 5, and between MnDD and MDD as 10.
The 15-item geriatric depression scale (GDS-15) is a short form of GDS and is used to screen, diagnose, and evaluate depression in elderly individuals. Most previous studies evaluated the ability of GDS-15 to discriminate between depressive and non-depressive states. In this study, we investigated the multi-stage discriminating ability of GDS-15.
A total of 774 participants, over 65 years of age were included (normal, n = 650; minor depressive disorder MnDD, n = 94; major depressive disorder MDD, n = 30). Multi-category receiver operating characteristic (ROC) surfaces were evaluated to identify three stages of geriatric depression. The optimal cutoff points were selected based on the volume under the ROC surface (VUS) and the Youden index.
In the results of multi-category classification analyses, VUS of the GDS-15 of 0.61 was obtained, and optimal cutoff points of the GDS-15 for multiple stages of depression of 4 (between normal and MnDD) and 11 (between MnDD and MDD) were derived. The Youden index for the GDS-15 was 0.49, and the derived optimal cutoff points were 5 and 10, for the multiple stages, respectively. The overall diagnostic accuracy based on the Youden index was superior to that based on the VUS in the GDS-15.
The participants’ cognitive function has potential to affect the GDS-15 score; nevertheless, the study included those with mild cognitive impairment.
GDS-15 was a useful tool to classify stages of geriatric depression into either minor or major depressive disorder.
Three unique hydroxybutyrate-containing triterpenoid saponins, angustiside A–C (1–3), were isolated from the shoots of Brachyscome angustifolia (Asteraceae). The extensive spectroscopic study showed ...that their aglycone is a previously undescribed one, 16-hydroxy olean-18-en-28-oic acid, named as angustic acid (1a), and 2 and 3 contain hydroxybutyrate moiety in their side chains. The absolute configuration of 1a was determined to be (3R,5R,9R,13S,16S) by X-ray crystallography. The immunity assay revealed that 2 and 3 containing both acyl chains and branched saccharides significantly enhanced the proliferation of OT-I CD8+ T cells and secretion of interferon gamma (IFN-γ), presenting their immunogenic activity.
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•Structurally novel C30-triterpenoid saponins from B. angustifolia were identified.•Absolute configuration was confirmed with X-ray crystallography, and cysteine and PGME reactions.•Angustiside B and C (2 and 3) showed immunogenic activity by inducing OT-I CD8+ T cells and IFN-γ response.
Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates ...the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported. In the current study, we used ERdj5-knockout mice to investigate the potential roles of ERdj5 in inflammatory bowel disease. ERdj5 deficiency causes severe inflammation in mouse colitis models and weakens gut barrier function by increasing NF-κB-mediated inflammation. ERdj5 may not be indispensable for goblet cell function under steady-state conditions, but its deficiency induces goblet cell apoptosis under inflammatory conditions. Treatment of ERdj5-knockout mice with the chemical chaperone ursodeoxycholic acid ameliorated severe colitis by reducing endoplasmic reticulum stress. These findings highlight the important role of ERdj5 in preserving goblet cell viability and function by resolving endoplasmic reticulum stress.
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