Akkermansia muciniphila phospholipid induces homeostatic immune responses.

Autor: Bae M; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.; College of Pharmacy, Gachon University, Incheon, South Korea., Cassilly CD; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA., Liu X; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Park SM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Tusi BK; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Chen X; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Kwon J; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.; Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Ganeung, South Korea., Filipčík P; Biochemistry Department, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.; SBGrid Consortium, Harvard Medical School, Blavatnik Institute, Boston, MA, USA., Bolze AS; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Liu Z; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Vlamakis H; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Graham DB; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Buhrlage SJ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Xavier RJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu., Clardy J; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA. jon_clardy@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Aug; Vol. 608 (7921), pp. 168-173. Date of Electronic Publication: 2022 Jul 27.
DOI: 10.1038/s41586-022-04985-7
Abstrakt: Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging 1-3 . Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity 4-7 . Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays 8 . The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer 9,10 . Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC 50 ) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: