| Title: | An LGR6 frameshift variant abrogates receptor expression on select leukocyte subsets and is associated with viral infections |
| Journal: | Blood |
| Published: | 25 Jul 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38718314/ |
| DOI: | https://doi.org/10.1182/blood.2023021826 |
| URL: | https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023021826/2224858/blood.2023021826.pdf |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 12129
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Abstract
ABSTRACT: The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) was recently identified as the cognate receptor for the proresolving mediator maresin 1 (MaR1). To address the biological role of LGR6 in humans, we investigated the functional impact of a genetic variant in the gene encoding for LGR6, which is predicted to lead to a frameshift mutation in one of the receptor isoforms, on both receptor expression and immune cell responses. In neutrophils, monocytes, and natural killer (NK) cells from volunteers homozygous for this variant, we found a significant downregulation in the expression of LGR6 when compared with controls without the variant; whereas the LGR6 expression was essentially similar in monocyte-derived macrophages and CD8+ T cells. Functionally, loss of LGR6 expression was linked with a decreased ability of neutrophils and monocytes to phagocytose bacteria. We observed an increase in neutrophil chemotaxis and leukotriene B4 production and increased expression of activation markers, including markers for platelet-leukocyte phagocyte heterotypic aggregates, such as CD41, in neutrophils and monocytes from the variant group. Using data from the UK Biobank, we found that at a population level the rs4266947 variant, which is in high linkage disequilibrium with rs74355478, was associated with a higher incidence of viral infections. Intriguingly, neutrophils, NK cells, and CD8+ T cells from volunteers with the LGR6 variant displayed altered viral responses when stimulated with Toll-like receptor 3 (TLR3), TLR7/TLR8, and TLR9 agonists. Together, these findings shed new light on the cell type-specific regulation of LGR6 expression and the role of this receptor in directing host immune responses.</p>
14 Keywords
- Adult
- CD8-Positive T-Lymphocytes
- Female
- Frameshift Mutation
- Humans
- Killer Cells, Natural
- Leukocytes
- Male
- Middle Aged
- Monocytes
- Neutrophils
- Phagocytosis
- Receptors, G-Protein-Coupled
- Virus Diseases
73 Authors
- Esteban A. Gomez
- Roberta De Matteis
- Palita Udomjarumanee
- Genes and Health Research Team
- Shaheen Akhtar
- Mohammad Anwar
- Elena Arciero
- Omar Asgar
- Samina Ashraf
- Saeed Bidi
- Gerome Breen
- James Broster
- Shabana Chaudhary
- Raymond Chung
- Megan Clinch
- David Collier
- Grainne Colligan
- Charles J. Curtis
- Panos Deloukas
- Ceri Durham
- Faiza Durrani
- Fabiola Eto
- Sarah Finer
- Joseph Gafton
- Ana Cristina Angel Garcia
- Chris Griffiths
- Joanne Harvey
- David A. van Heel
- Teng Heng
- Sam Hodgson
- Qin Qin Huang
- Matt Hurles
- Karen A Hunt
- Shapna Hussain
- Kamrul Islam
- Vivek Iyer
- Benjamin M. Jacobs
- Ahsan Khan
- Claudia Langenberg
- Cath Lavery
- Sang Hyuck Lee
- Daniel MacArthur
- Sidra Malik
- Daniel Malawsky
- Hilary Martin
- Dan Mason
- Rohini Mathur
- Mohammed Bodrul Mazid
- John McDermott
- Caroline Morton
- Bill Newman
- Elizabeth Owor
- Asma Qureshi
- Shwetha Ramachandrappa
- Mehru Raza
- Jessry Russell
- Nishat Safa
- Miriam Samuel
- Michael Simpson
- John Solly
- Marie Spreckley
- Daniel Stow
- Michael Taylor
- Richard C. Trembath
- Karen Tricker
- Klaudia Walter
- Caroline Winckley
- Suzanne Wood
- John Wright
- Ishevanhu Zengeya
- Julia Zöllner
- Patricia B. Munroe
- Jesmond Dalli
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