Microbiota Translocation Following Intestinal Barrier Disruption Promotes Mincle-mediated Training of Myeloid Progenitors in the Bone Marrow

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.

References

Macpherson A, Uhr T . Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science. 2004; 303(5664):1662-5. DOI: 10.1126/science.1091334. View

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N . Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018; 359(6380):1156-1161. PMC: 5959731. DOI: 10.1126/science.aar7201. View

Buenrostro J, Wu B, Chang H, Greenleaf W . ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. Curr Protoc Mol Biol. 2015; 109:21.29.1-21.29.9. PMC: 4374986. DOI: 10.1002/0471142727.mb2129s109. View

Schulthess J, Pandey S, Capitani M, Rue-Albrecht K, Arnold I, Franchini F . The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity. 2019; 50(2):432-445.e7. PMC: 6382411. DOI: 10.1016/j.immuni.2018.12.018. View

Ishikawa T, Itoh F, Yoshida S, Saijo S, Matsuzawa T, Gonoi T . Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia. Cell Host Microbe. 2013; 13(4):477-88. DOI: 10.1016/j.chom.2013.03.008. View

Efremova M, Vento-Tormo M, Teichmann S, Vento-Tormo R . CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc. 2020; 15(4):1484-1506. DOI: 10.1038/s41596-020-0292-x. View

Jensen S, Paerregaard S, Brandum E, Jorgensen A, Hjorto G, Jensen B . Rewiring host-microbe interactions and barrier function during gastrointestinal inflammation. Gastroenterol Rep (Oxf). 2022; 10(1):goac008. PMC: 8915887. DOI: 10.1093/gastro/goac008. View

Martin-Cruz L, Sevilla-Ortega C, Benito-Villalvilla C, Diez-Rivero C, Sanchez-Ramon S, Subiza J . A Combination of Polybacterial MV140 and V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections. Front Immunol. 2021; 11:612269. PMC: 7858650. DOI: 10.3389/fimmu.2020.612269. View

10.

Sokol H, Leducq V, Aschard H, Pham H, Jegou S, Landman C . Fungal microbiota dysbiosis in IBD. Gut. 2016; 66(6):1039-1048. PMC: 5532459. DOI: 10.1136/gutjnl-2015-310746. View

11.

Akdis C . Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?. Nat Rev Immunol. 2021; 21(11):739-751. DOI: 10.1038/s41577-021-00538-7. View

12.

Ziogas A, Netea M . Trained immunity-related vaccines: innate immune memory and heterologous protection against infections. Trends Mol Med. 2022; 28(6):497-512. DOI: 10.1016/j.molmed.2022.03.009. View

13.

Sancho D, Mourao-Sa D, Joffre O, Schulz O, Rogers N, Pennington D . Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J Clin Invest. 2008; 118(6):2098-110. PMC: 2391066. DOI: 10.1172/JCI34584. View

14.

Sancho D, Reis e Sousa C . Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol. 2012; 30:491-529. PMC: 4480235. DOI: 10.1146/annurev-immunol-031210-101352. View

15.

Quintin J, Saeed S, Martens J, Giamarellos-Bourboulis E, Ifrim D, Logie C . Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012; 12(2):223-32. PMC: 3864037. DOI: 10.1016/j.chom.2012.06.006. View

16.

de la Visitacion N, Robles-Vera I, Moleon J, Gonzalez-Correa C, Aguilera-Sanchez N, Toral M . Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity. Antioxidants (Basel). 2021; 10(9). PMC: 8472682. DOI: 10.3390/antiox10091426. View

17.

Hand T, Dos Santos L, Bouladoux N, Molloy M, Pagan A, Pepper M . Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. 2012; 337(6101):1553-6. PMC: 3784339. DOI: 10.1126/science.1220961. View

18.

Arts R, Moorlag S, Novakovic B, Li Y, Wang S, Oosting M . BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018; 23(1):89-100.e5. DOI: 10.1016/j.chom.2017.12.010. View

19.

Deshmukh H, Liu Y, Menkiti O, Mei J, Dai N, OLeary C . The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med. 2014; 20(5):524-30. PMC: 4016187. DOI: 10.1038/nm.3542. View

20.

Bekkering S, Dominguez-Andres J, Joosten L, Riksen N, Netea M . Trained Immunity: Reprogramming Innate Immunity in Health and Disease. Annu Rev Immunol. 2021; 39:667-693. DOI: 10.1146/annurev-immunol-102119-073855. View