Gadd45β promotes regeneration after injury through TGFβ-dependent restitution in experimental colitis.
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ABSTRACT:
SUBMITTER: Hwang JH
PROVIDER: S-EPMC6821912 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disease of the gastrointestinal tract, characterized by cycles of acute flares, recovery and remission phases. Treatments for accelerating tissue restitution and prolonging remission are scarce, but altering the microbiota composition to promote intestinal homeostasis is considered a safe, economic and promising approach. Although probiotic bacteria have not yet fulfilled fully their promise in clinical trials, understanding the mechanism of how they exert beneficial effects will permit devising improved therapeutic strategies. Here we probe if one of the defining features of lactobacilli, the ability to generate nanomolar H2O2, contributes to their beneficial role in colitis. H2O2 generation by wild type L. johnsonii was modified by either deleting or overexpressing the enzymatic H2O2 source(s) followed by orally administering the bacteria before and during DSS colitis. Boosting luminal H2O2 concentrations within a physiological range accelerated recovery from colitis, while significantly exceeding this H2O2 level triggered bacteraemia. This study supports a role for increasing H2O2 within the physiological range at the epithelial barrier, independently of the enzymatic source and/or delivery mechanism, for inducing recovery and remission in IBD.
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Project description:Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
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Project description:Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1ΔIEC) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3-4-week-old DKO;Dclk1ΔIEC mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1ΔIEC relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1ΔIEC mice at 3-6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa.
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Project description:Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible β (Gadd45β)-dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet- or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.
| S-EPMC7953268 | biostudies-literature
Project description:BackgroundThe etiology of sporadic Parkinson's disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention.MethodsWe sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)-an inhibitor of nuclear factor kappa B (NFκB)-to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted.ResultsHigh levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology.ConclusionsThis study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice.
| S-EPMC8375080 | biostudies-literature
Project description:Macroautophagy/autophagy is essential for maintaining cellular homeostasis through the degradation of organelles and proteins. It also has a prominent role in modulating aging. However, the role of autophagy in the neuronal response to axon injury and axon regeneration, particularly in the context of aging, remains largely unknown. Our candidate genetic screen for axon regeneration regulators has identified genes in the autophagy pathway. Using a reporter that monitors autophagosomes and autolysosomes, we were able to monitor the dynamics of autophagy during axon regeneration. In response to axon injury, there was a significant increase in the number of autophagic vesicles. Injury-triggered autophagy activation and axon regeneration capacity undergo an age-dependent decline, and autophagy-activating agents partially rescued these declines. We found that DLK-1 was both required and sufficient for injury-induced autophagy activation. Autophagic vesicles co-localized with the NOTCH4 ortholog, LIN-12 receptor, a previously identified inhibitor of axon regeneration. Epistasis analyses indicate that LIN-12 might be a target of autophagy in axon regeneration. Together, our data suggest that DLK-mediated injury signaling can activate autophagy, which might limit the level of LIN-12 and NOTCH proteins to promote axon regeneration. Our findings reveal that autophagy activation can promote axon regeneration in neurons that lack maximal regrowth capacity, providing a promising therapeutic strategy for axon injury. Abbreviations: 3-MA: 3-methyladenine; ALs: autolysosomes; APs: autophagosomes; ARF-6: ADP-Ribosylation Factor related 6; ATG-9: AuTophaGy (yeast Atg homolog) 9; ATG9A: autophagy related 9A; BA1: bafilomycin A1; BEC-1: BEClin (human autophagy) homolog; BECN1: beclin 1; C. elegans: Caenorhabditis elegans; CEBP-1: C/EBP (CCAAT/enhancer-binding protein) homolog; CNS: central nervous system; DLK-1: Dual-Leucine zipper Kinase; DMSO: dimethyl sulfoxide; DRG: dorsal root ganglion; FOS: Fos proto-oncogene, AP-1 transcription factor subunit; GABA: gamma-aminobutyric acid; GFP: green fluorescent protein; HDA-3: Histone DeAcetylase; IP3: inositol trisphosphate; ITR-1: Inositol Triphosphate Receptor; KLF-2: Kruppel-Like Factor (zinc finger protein) 2; LGG-1: LC3, GABARAP and GATE-16 family; MAK-2: MAP kinase Activated protein Kinase; MAP kinase: mitogen-activated protein kinase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKK-4: mitogen activated protein kinase kinase 4; MTOR: mechanistic target of rapamycin kinase; NGM: nematode growth medium; NICD: Notch intracellular domain; NOTCH: notch receptor; PLM: posterior lateral microtubule; PMK-3: P38 Map kinase family; PNS: peripheral nervous system; SCG10: superior cervical ganglion protein 10; SCI: spinal cord injury; UNC-51: UNCoordinated 51; ULK1: unc-51 like autophagy activating kinase 1; wnd: wallenda.
| S-EPMC7595581 | biostudies-literature
Project description:Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1-/- mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain intestinal immune homeostasis. Here, we generated dendritic cell (DC)-specific Ripk1-/- mice in a genetic background with loss of RIPK1 kinase activity and found that the mice developed spontaneous colonic inflammation characterized by increased neutrophil and Ly6C+ monocytes. In addition, these mice were highly resistant to injury-induced colitis. The increased colonic inflammation and the resistance to colitis were restored by dual inactivation of RIPK3 and FADD, but not by inhibition of RIPK3, MLKL, or ZBP1 alone. Altogether, these results reveal a scaffold activity-dependent role of RIPK1 in DC-mediated maintenance of colonic immune homeostasis.
| S-EPMC8732271 | biostudies-literature
Project description:BACKGROUND & AIMS:Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known. METHODS:With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction. RESULTS:In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor. CONCLUSIONS:The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.
| S-EPMC2533811 | biostudies-literature
Project description:Restoration of lost function following a nervous system injury is limited in adulthood as the regenerative capacity of nervous system declines with age. Pharmacological approaches have not been very successful in alleviating the consequences of nervous system injury. On the contrary, physical activity and rehabilitation interventions are often beneficial to improve the health conditions in the patients with neuronal injuries. Using touch neuron circuit of Caenorhabditis elegans, we investigated the role of physical exercise in the improvement of functional restoration after axotomy. We found that a swimming session of 90 min following the axotomy of posterior lateral microtubule (PLM) neuron can improve functional recovery in larval and adult stage animals. In older age, multiple exercise sessions were required to enhance the functional recovery. Genetic analysis of axon regeneration mutants showed that exercise-mediated enhancement of functional recovery depends on the ability of axon to regenerate. Exercise promotes early initiation of regrowth, self-fusion of proximal and distal ends, as well as postregrowth enhancement of function. We further found that the swimming exercise promotes axon regeneration through the activity of cellular energy sensor AAK-2/AMPK in both muscle and neuron. Our study established a paradigm where systemic effects of exercise on functional regeneration could be addressed at the single neuron level.
| S-EPMC8211466 | biostudies-literature
Project description:Background & aimsChronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFβ, since TGFβ signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis.MethodsWild-type mice underwent 70% partial hepatectomy (PH); TGFβ expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72 h after PH. To determine the role of Yap1 in regulating TGFβ signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice.ResultsTGFβ expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation.ConclusionInteractions between the TGFβ and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFβ-enriched microenvironment and regenerate injured livers.Lay summaryThe adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.
| S-EPMC6349217 | biostudies-literature