AI Article Synopsis
- The study investigates the role of PI3K p110δ in regulating innate immune responses and preventing chronic inflammation, as shown in a mouse model with a specific genetic mutation.
- Mice with the mutation exhibited progressive colitis, marked by increased colonic inflammation and altered immune signaling as they aged.
- The findings suggest that PI3K p110δ is essential for maintaining mucosal homeostasis and could be relevant for understanding inflammatory bowel diseases in humans.
Article Abstract
Background & Aims: Innate immune responses are crucial for host defense against pathogens but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110δ subunit of phosphoinositide 3-kinase (PI3K p110δ(D910A/D910A)) revealed defects in B- and T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases in these mice and investigate underlying innate immune defects.
Methods: Colons and macrophages from PI3K p110δ(D910A/D910A) mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110δ messenger RNA expression was examined in interleukin (IL)-10(-/-) and wild-type germ-free mice during transition to a conventional microbiota. To assess polygenic impact on development of colitis, p110δ(D910A/D910A) mice were backcrossed to IL-10(-/-) mice.
Results: A mild spontaneous colitis was shown in PI3K p110δ(D910A/D910A) mice at 8 weeks, with inflammation increasing with age. An inflammatory mucosal and systemic cytokine profile was characterized by expression of IL-12/23. In PI3K p110δ(D910A/D910A) macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110δ, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110δ expression with the introduction of the enteric microbiota; however, colitis-prone IL-10(-/-) mice did not. Moreover, PI3K p110δ(D910A/D910A) mice crossed to IL-10(-/-) mice developed severe colitis at an early age.
Conclusions: This study describes a novel model of experimental colitis that highlights the importance of PI3K p110δ in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967619 | PMC |
| http://dx.doi.org/10.1053/j.gastro.2010.07.008 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A combined opposite targeting of p110δ PI3K and RhoA abrogates skin cancer.
Commun Biol
January 2024
Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece.
Malignant melanoma is the most aggressive and deadly skin cancer with an increasing incidence worldwide whereas SCC is the second most common non-melanoma human skin cancer with limited treatment options. Here we show that the development and metastasis of melanoma and SCC cancers can be blocked by a combined opposite targeting of RhoA and p110δ PI3K. We found that a targeted induction of RhoA activity into tumours by deletion of p190RhoGAP-a potent inhibitor of RhoA GTPase-in tumour cells together with adoptive macrophages transfer from δ mice in mice bearing tumours with active RhoA abrogated growth progression of melanoma and SCC tumours.
View Article and Find Full Text PDFLack of Functional P110δ Affects Expression of Activation Marker CD80 but Does Not Influence Functions of Neutrophils.
Int J Mol Sci
June 2022
Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Zwirki i Wigury 63a Street, 02-091 Warsaw, Poland.
Neutrophils are specialized immune cells that are essential constituents of the innate immune response. They defend the organism against pathogens through various mechanisms. It was reported that phosphatidylinositols are key players in neutrophil functions, especially in the activity of class-I phosphoinositide 3-kinases (PI3Ks).
View Article and Find Full Text PDFPhosphoinositide 3-Kinase P110δ-Signaling Is Critical for Microbiota-Activated IL-10 Production by B Cells that Regulate Intestinal Inflammation.
Cells
September 2019
Center for Gastrointestinal Biology and Disease, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
The phosphoinositide 3-kinase catalytic subunit p110δ (PI3Kδ) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3Kδ signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3Kδ on IL-10-producing B cells that help regulate mucosal inflammation in IBD. We investigated the role of PI3Kδ signaling in B cell production of IL-10, following stimulation by resident bacteria and B cell regulatory function against colitis.
View Article and Find Full Text PDFp110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model.
J Neurosci
October 2019
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia,
Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored.
View Article and Find Full Text PDFPI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression.
J Clin Invest
January 2019
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy.
Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!