scholarly journals IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

2017 ◽  
Vol 214 (2) ◽  
pp. 423-437 ◽  
Author(s):  
Michaela A. Diamanti ◽  
Jalaj Gupta ◽  
Moritz Bennecke ◽  
Tiago De Oliveira ◽  
Mallika Ramakrishnan ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
Epithelial Regeneration ◽  
Iκb Kinase ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Protein Response ◽  
Oligomerization Domain

Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.

scholarly journals Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism

2018 ◽  
Vol 115 (43) ◽  
pp. 11036-11041 ◽  
Author(s):  
Yasuharu Nagahama ◽  
Mayuko Shimoda ◽  
Guoliang Mao ◽  
Shailendra Kumar Singh ◽  
Yuuki Kozakai ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Body Weight Loss ◽  
Purine Metabolism ◽  
Intestinal Epithelial ◽  
Beneficial Effects ◽  
Epithelial Regeneration ◽  
Mtorc1 Signaling ◽  
Inflammatory Bowel

Damage to intestinal epithelial cell (IEC) layers during intestinal inflammation is associated with inflammatory bowel disease. Here we show that the endoribonuclease Regnase-1 controls colon epithelial regeneration by regulating protein kinase mTOR (the mechanistic target of rapamycin kinase) and purine metabolism. During dextran sulfate sodium-induced intestinal epithelial injury and acute colitis, Regnase-1∆IEC mice, which lack Regnase-1 specifically in the intestinal epithelium, were resistant to body weight loss, maintained an intact intestinal barrier, and showed increased cell proliferation and decreased epithelial apoptosis. Chronic colitis and tumor progression were also attenuated in Regnase-1∆IEC mice. Regnase-1 predominantly regulates mTORC1 signaling. Metabolic analysis revealed that Regnase-1 participates in purine metabolism and energy metabolism during inflammation. Furthermore, increased expression of ectonucleotidases contributed to the resolution of acute inflammation in Regnase-1∆IEC mice. These findings provide evidence that Regnase-1 deficiency has beneficial effects on the prevention and/or blocking of intestinal inflammatory disorders.

scholarly journals The Multifaceted Role of the Inflammasome in Inflammatory Bowel Diseases

2011 ◽  
Vol 11 ◽  
pp. 1536-1547 ◽  
Author(s):  
Donata Lissner ◽  
Britta Siegmund
Keyword(s):  
Inflammatory Bowel Disease ◽  
Inflammatory Bowel Diseases ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
Specific Cell ◽  
Epithelial Regeneration ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Inflammasomes are intracellular multiprotein complexes that coordinate the maturation of interleukin (IL)-1β and IL-18 in response to pathogens and metabolic danger. Both cytokines have been linked to intestinal inflammation. However, recently evolving concepts ascribe a major role to the inflammasome in maintaining intestinal homeostasis. This review recapitulates its position in the development of inflammatory bowel disease, thereby outlining a model in which hypo- as well as hyperfunctionality can lead to an imbalance of the system, depending on the specific cell population affected. In the epithelium, the inflammasome is essential for regulation of permeability and epithelial regeneration through sensing of commensal microbes, while excessive inflammasome activation within the lamina propria contributes to severe intestinal inflammation.

ER stress and the unfolded protein response in intestinal inflammation

2010 ◽  
Vol 298 (6) ◽  
pp. G820-G832 ◽  
Author(s):  
Michael A. McGuckin ◽  
Rajaraman D. Eri ◽  
Indrajit Das ◽  
Rohan Lourie ◽  
Timothy H. Florin
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Intestinal Inflammation ◽  
Secretory Cells ◽  
Unfolded Protein ◽  
Bowel Diseases ◽  
Stressed Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress is a phenomenon that occurs when excessive protein misfolding occurs during biosynthesis. ER stress triggers a series of signaling and transcriptional events known as the unfolded protein response (UPR). The UPR attempts to restore homeostasis in the ER but if unsuccessful can trigger apoptosis in the stressed cells and local inflammation. Intestinal secretory cells are susceptible to ER stress because they produce large amounts of complex proteins for secretion, most of which are involved in mucosal defense. This review focuses on ER stress in intestinal secretory cells and describes how increased protein misfolding could occur in these cells, the process of degradation of misfolded proteins, the major molecular elements of the UPR pathway, and links between the UPR and inflammation. Evidence is reviewed from mouse models and human inflammatory bowel diseases that ties ER stress and activation of the UPR with intestinal inflammation, and possible therapeutic approaches to ameliorate ER stress are discussed.

scholarly journals Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

2018 ◽  
Vol 116 (3) ◽  
pp. 970-975 ◽  
Author(s):  
Yue Li ◽  
Marita Führer ◽  
Ehsan Bahrami ◽  
Piotr Socha ◽  
Maja Klaudel-Dreszler ◽  
...  
Keyword(s):  
Cell Death ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Monogenic Disorders ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Human Immune

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

scholarly journals Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection?

2020 ◽  
Vol 14 (9) ◽  
pp. 1334-1336 ◽  
Author(s):  
Giovanni Monteleone ◽  
Sandro Ardizzone
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Convincing Evidence ◽  
Complex Interaction ◽  
The Novel ◽  
Relevant Today ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Patients At Risk ◽  
Inflammatory Bowel

Abstract Crohn’s disease [CD] and ulcerative colitis [UC], the main inflammatory bowel diseases [IBD] in humans, are chronic, immune-inflammatory diseases, the pathogenesis of which suggests a complex interaction between environmental factors and genetic susceptibility. These disabling conditions affect millions of individuals and, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions. This is particularly relevant today, as coronavirus disease [Covid-19] has rapidly spread from China to countries where IBD are more prevalent, and there is convincing evidence that Covid-19-mediated morbidity and mortality are higher in subjects with comorbidities. The primary objectives of this Viewpoint are to provide a focused overview of the factors and mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infects cells and to illustrate the link between such determinants and intestinal inflammation. We also provide clues about the reasons why the overall IBD population might have no increased risk of developing SARS-CoV-2 infection and highlight the potential of cytokine blockers, used to treat IBD patients, to prevent Covid-driven pneumonia.

scholarly journals Understanding the Pathogenesis of Spondyloarthritis

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1461
Author(s):  
Aigul Sharip ◽  
Jeannette Kunz
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endoplasmic Reticulum ◽  
Psoriatic Arthritis ◽  
Ankylosing Spondylitis ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Unfolded Protein ◽  
Exact Etiology ◽  
Inflammatory Bowel ◽  
Protein Response

Spondyloarthritis comprises a group of inflammatory diseases of the joints and spine, with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B*27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B*27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B*27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

scholarly journals Understanding the Pathogenesis of Spondyloarthritis

2020 ◽  
Author(s):  
Aigul Sharip ◽  
Jeannette Kunz
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endoplasmic Reticulum ◽  
Psoriatic Arthritis ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Hla B27 ◽  
Unfolded Protein ◽  
Exact Etiology ◽  
Inflammatory Bowel ◽  
Protein Response

Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

scholarly journals A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival

2018 ◽  
Vol 215 (7) ◽  
pp. 1839-1852 ◽  
Author(s):  
Michael G. Kattah ◽  
Ling Shao ◽  
Yenny Y. Rosli ◽  
Hiromichi Shimizu ◽  
Michael I. Whang ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Kinase Activity ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Intestinal Epithelial ◽  
Tissue Integrity ◽  
Caspase Inhibition ◽  
Inflammatory Bowel

A20 (TNFAIP3) and ABIN-1 (TNIP1) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.

scholarly journals Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Albert E. Jergens ◽  
Shadi Parvinroo ◽  
Jamie Kopper ◽  
Michael J. Wannemuehler
Keyword(s):  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Disease Onset ◽  
Intestinal Epithelial ◽  
Bowel Diseases ◽  
Exact Etiology ◽  
Mucosal Homeostasis ◽  
Inflammatory Bowel ◽  
And Function ◽  
Iga Production

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex, multifactorial disorders that lead to chronic and relapsing intestinal inflammation. The exact etiology remains unknown, however multiple factors including the environment, genetic, dietary, mucosal immunity, and altered microbiome structure and function play important roles in disease onset and progression. Supporting this notion that the gut microbiota plays a pivotal role in IBD pathogenesis, studies in gnotobiotic mice have shown that mouse models of intestinal inflammation require a microbial community to develop colitis. Additionally, antimicrobial therapy in some IBD patients will temporarily induce remission further demonstrating an association between gut microbes and intestinal inflammation. Finally, a dysfunctional intestinal epithelial barrier is also recognized as a key pathogenic factor in IBD. The intestinal epithelium serves as a barrier between the luminal environment and the mucosal immune system and guards against harmful molecules and microorganisms while being permeable to essential nutrients and solutes. Beneficial (i.e., mutualists) bacteria promote mucosal health by strengthening barrier integrity, increasing local defenses (mucin and IgA production) and inhibiting pro-inflammatory immune responses and apoptosis to promote mucosal homeostasis. In contrast, pathogenic bacteria and pathobionts suppress expression and localization of tight junction proteins, cause dysregulation of apoptosis/proliferation and increase pro-inflammatory signaling that directly damages the intestinal mucosa. This review article will focus on the role of intestinal epithelial cells (IECs) and the luminal environment acting as mediators of barrier function in IBD. We will also share some of our translational observations of interactions between IECs, immune cells, and environmental factors contributing to maintenance of mucosal homeostasis, as it relates to GI inflammation and IBD in different animal models.

scholarly journals Roles of Macrophages in the Development and Treatment of Gut Inflammation

2021 ◽  
Vol 9 ◽  
Author(s):  
Xuebing Han ◽  
Sujuan Ding ◽  
Hongmei Jiang ◽  
Gang Liu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Inflammatory Response ◽  
Intestinal Tract ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Inflammatory Diseases ◽  
Clear Understanding ◽  
Intestinal Epithelial ◽  
Functional Plasticity ◽  
Inflammatory Bowel

Macrophages, which are functional plasticity cells, have the ability to phagocytize and digest foreign substances and acquire pro-(M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. The large number of macrophages in the intestinal tract, play a significant role in maintaining the homeostasis of microorganisms on the surface of the intestinal mucosa and in the continuous renewal of intestinal epithelial cells. They are not only responsible for innate immunity, but also participate in the development of intestinal inflammation. A clear understanding of the function of macrophages, as well as their role in pathogens and inflammatory response, will delineate the next steps in the treatment of intestinal inflammatory diseases. In this review, we discuss the origin and development of macrophages and their role in the intestinal inflammatory response or infection. In addition, the effects of macrophages in the occurrence and development of inflammatory bowel disease (IBD), and their role in inducing fibrosis, activating T cells, reducing colitis, and treating intestinal inflammation were also reviewed in this paper.

Sign in / Sign up

Export Citation Format

Share Document