Title | ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Guillet S, Lazarov T, Jordan N, Boisson B, Tello M, Craddock B, Zhou T, Nishi C, Bareja R, Yang H, Rieux-Laucat F, Lorenzo RIrene Freg, Dyall SD, Isenberg D, D'Cruz D, Lachmann N, Elemento O, Viale A, Socci ND, Abel L, Nagata S, Huse M, W Miller T, Casanova J-L, Geissmann F |
Journal | Elife |
Volume | 13 |
Date Published | 2024 Nov 21 |
ISSN | 2050-084X |
Keywords | Adult, Animals, Autoantibodies, c-Mer Tyrosine Kinase, Disease Models, Animal, Efferocytosis, Female, Humans, Lupus Erythematosus, Systemic, Macrophages, Male, Mice, Phagocytosis, Protein-Tyrosine Kinases |
Abstract | Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages. |
DOI | 10.7554/eLife.96085 |
Alternate Journal | Elife |
PubMed ID | 39570652 |
PubMed Central ID | PMC11581429 |
Grant List | Annee Recherche / / Assistance Publique - Hôpitaux de Paris / R01 AI124349 / AI / NIAID NIH HHS / United States 5R01AI124349-03 / / National Institute of Allergy and Infectious Diseases / JPMJCR14M4 / / Core Research for Evolutional Science and Technology / P30CA008748 / CA / NCI NIH HHS / United States 1R01AI130345-01 / / National Institute of Allergy and Infectious Diseases / R01 AI130345 / AI / NIAID NIH HHS / United States R01 CA058530 / CA / NCI NIH HHS / United States R01-AI087644 / / National Institute of Allergy and Infectious Diseases / DEA20140630127 / / Fondation pour la Recherche Médicale / CA58530 / CA / NCI NIH HHS / United States No. 15H05785 / / Grants-in-Aid for Scientific Research / Fellowship / ARC_ / Arthritis Research UK / United Kingdom R01 AI087644 / AI / NIAID NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States |