Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow

  • Immunity. 2025 Jan 16:S1074-7613(24)00577-6. doi: 10.1016/j.immuni.2024.12.012.
Iñaki Robles-Vera  1 ,  Aitor Jarit-Cabanillas  2 ,  Paola Brandi  3 ,  María Martínez-López  3 ,  Sarai Martínez-Cano  4 ,  Manuel Rodrigo-Tapias  3 ,  Marcos Femenía-Muiña  3 ,  Ana Redondo-Urzainqui  3 ,  Vanesa Nuñez  3 ,  Cristina González-Correa  5 ,  Javier Moleón  5 ,  Juan Duarte  5 ,  Laura Conejero  6 ,  Pablo Mata-Martínez  7 ,  Carmen María Díez-Rivero  6 ,  Marta Bergón-Gutiérrez  7 ,  Iván Fernández-López  3 ,  Manuel J Gómez  3 ,  Ana Quintas  3 ,  Ana Dopazo  3 ,  Fátima Sánchez-Cabo  3 ,  Esther Pariente  3 ,  Carlos Del Fresno  7 ,  José Luis Subiza  6 ,  Salvador Iborra  8 ,  David Sancho  9
Affiliations
  • 1. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address: [email protected].
  • 2. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 12 de Octubre Health Research Institute (imas12), Madrid, Spain.
  • 3. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 4. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Inmunotek S.L., Alcalá de Henares, Spain.
  • 5. Department of Pharmacology, School of Pharmacy, University of Granada, IBS-Granada, Centro de Investigaciones Biomédicas (CIBM), CIBER-Enfermedades Cardiovasculares (CiberCV), Granada, Spain.
  • 6. Inmunotek S.L., Alcalá de Henares, Spain.
  • 7. Immunomodulation Lab, Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.
  • 8. Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 12 de Octubre Health Research Institute (imas12), Madrid, Spain; Fundación Inmunotek, Alcalá de Henares, Spain.
  • 9. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address: [email protected].
PMID: 39848243 DOI: 10.1016/j.immuni.2024.12.012
Abstract

Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that Enterococcus faecalis translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed E. faecalis reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses in vitro and in vivo and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (Clec4e) was essential for E. faecalis-induced TI in BMPs. Clec4e-/- mice showed impaired TI upon E. faecalis administration and reduced pathology following DSS treatment. Thus, Mincle sensing of E. faecalis induces TI that may have long-term effects on pathologies associated with increased gut permeability.

Keywords
Mincle receptor; bone marrow progenitors; gut bacterial translocation; inflammation; macrophages; trained immunity.
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