Vascular traffic control of neutrophil recruitment to the liver by microbiota-endothelium crosstalk
Amanda Z. Zucoloto,
Jared Schlechte,
Aline Ignacio,
Carolyn A. Thomson,
Shannon Pyke,
Ian-ling Yu,
Markus B. Geuking,
Kathy D. McCoy,
Bryan G. Yipp,
Mark R. Gillrie,
Braedon McDonald
Affiliations
Amanda Z. Zucoloto
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Jared Schlechte
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Aline Ignacio
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Carolyn A. Thomson
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Shannon Pyke
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Ian-ling Yu
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Markus B. Geuking
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Kathy D. McCoy
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Bryan G. Yipp
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Mark R. Gillrie
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Braedon McDonald
Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Corresponding author
Summary: During bloodstream infections, neutrophils home to the liver as part of an intravascular immune response to eradicate blood-borne pathogens, but the mechanisms regulating this crucial response are unknown. Using in vivo imaging of neutrophil trafficking in germ-free and gnotobiotic mice, we demonstrate that the intestinal microbiota guides neutrophil homing to the liver in response to infection mediated by the microbial metabolite D-lactate. Commensal-derived D-lactate augments neutrophil adhesion in the liver independent of granulopoiesis in bone marrow or neutrophil maturation and activation in blood. Instead, gut-to-liver D-lactate signaling primes liver endothelial cells to upregulate adhesion molecule expression in response to infection and promote neutrophil adherence. Targeted correction of microbiota D-lactate production in a model of antibiotic-induced dysbiosis restores neutrophil homing to the liver and reduces bacteremia in a model of Staphylococcus aureus infection. These findings reveal long-distance traffic control of neutrophil recruitment to the liver by microbiota-endothelium crosstalk.
