Activated PI3K delta syndrome 1 mutations cause neutrophilia in zebrafish larvae.
| Title: | Activated PI3K delta syndrome 1 mutations cause neutrophilia in zebrafish larvae. |
|---|---|
| Authors: | Elworthy S; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Rutherford HA; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Prajsnar TK; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland.; Hamilton NM; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Vogt K; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Renshaw SA; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK.; Condliffe AM; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK. |
| Source: | Disease models & mechanisms [Dis Model Mech] 2023 Mar 01; Vol. 16 (3). Date of Electronic Publication: 2023 Mar 13. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Cambridge : Company of Biologists Ltd., c2008- |
| MeSH Terms: | Zebrafish*/genetics ; Bronchiectasis*; Primary Immunodeficiency Diseases ; Mutation ; Humans ; Neutrophils ; Mice ; Phosphatidylinositol 3-Kinases ; Class I Phosphatidylinositol 3-Kinases ; Animals |
| Abstract: | People with activated PI3 kinase delta syndrome 1 (APDS1) suffer from immune deficiency and severe bronchiectasis. APDS1 is caused by dominant activating mutations of the PIK3CD gene that encodes the PI3 kinase delta (PI3Kδ) catalytic subunit. Despite the importance of innate immunity defects in bronchiectasis, there has been limited investigation of neutrophils or macrophages in APDS1 patients or mouse models. Zebrafish embryos provide an ideal system to study neutrophils and macrophages. We used CRISPR-Cas9 and CRISPR-Cpf1, with oligonucleotide-directed homologous repair, to engineer zebrafish equivalents of the two most prevalent human APDS1 disease mutations. These zebrafish pik3cd alleles dominantly caused excessive neutrophilic inflammation in a tail-fin injury model. They also resulted in total body neutrophilia in the absence of any inflammatory stimulus but normal numbers of macrophages. Exposure of zebrafish to the PI3Kδ inhibitor CAL-101 reversed the total body neutrophilia. There was no apparent defect in neutrophil maturation or migration, and tail-fin regeneration was unimpaired. Overall, the finding is of enhanced granulopoeisis, in the absence of notable phenotypic change in neutrophils and macrophages.; (© 2023. Published by The Company of Biologists Ltd.) |
| Competing Interests: | Competing interests The authors declare no competing or financial interests. |
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| Grant Information: | MR/M012328/2 United Kingdom MRC_ Medical Research Council; MR/N02995X/1 United Kingdom MRC_ Medical Research Council; MR/P020941/1 United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Keywords: APDS; CRISPR; Cas12a; Cpf1; Homology-directed gene editing; Neutrophil; Neutrophilia; PI3K delta; Zebrafish |
| Substance Nomenclature: | EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) |
| SCR Disease Name: | Activated PI3K-delta Syndrome |
| Entry Date(s): | Date Created: 20230222 Date Completed: 20230314 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10655814 |
| DOI: | 10.1242/dmm.049841 |
| PMID: | 36805642 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't