Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.
Journal
Mucosal immunology
ISSN: 1935-3456
Titre abrégé: Mucosal Immunol
Pays: United States
ID NLM: 101299742
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
11
01
2022
accepted:
24
08
2022
revised:
11
08
2022
pubmed:
28
10
2022
medline:
1
12
2022
entrez:
27
10
2022
Statut:
ppublish
Résumé
Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.
Identifiants
pubmed: 36302964
doi: 10.1038/s41385-022-00572-1
pii: S1933-0219(22)01765-2
pmc: PMC9607658
doi:
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
Lipids
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1431-1446Subventions
Organisme : Wellcome Trust
ID : 211276/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 218597/Z/19/Z
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 222426/Z/21/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211122/Z/18/Z
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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