MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection.
Listeria monocytogenes is a food-borne bacterial pathogen that causes systemic infection by traversing the intestinal mucosa. Although MyD88-mediated signals are essential for defense against systemic L. monocytogenes infection, the role of Toll-like receptor and MyD88 signaling in intestinal immunity against this pathogen has not been defined. We show that clearance of L. monocytogenes from the lumen of the distal small intestine is impaired in MyD88(-/-) mice. The distal ileum of wild-type (wt) mice expresses high levels of RegIII gamma, which is a bactericidal lectin that is secreted into the bowel lumen, whereas RegIII gamma expression in MyD88(-/-) mice is nearly undetectable. In vivo depletion of RegIII gamma from the small intestine of wt mice diminishes killing of luminal L. monocytogenes, whereas reconstitution of MyD88-deficient mice with recombinant RegIII gamma enhances intestinal bacterial clearance. Experiments with bone marrow chimeric mice reveal that MyD88-mediated signals in nonhematopoietic cells induce RegIII gamma expression in the small intestine, thereby enhancing bacterial killing. Our findings support a model of MyD88-mediated epithelial conditioning that protects the intestinal mucosa against bacterial invasion by inducing RegIII gamma.
Brandl
Katharina
K
Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Plitas
George
G
Schnabl
Bernd
B
DeMatteo
Ronald P
RP
Pamer
Eric G
EG
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000382:microbiology; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D037102:Lectins / Q000737:chemistry; D008089:Listeria monocytogenes / Q000378:metabolism*; D008088:Listeriosis / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology*; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
D037102:Lectins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D011994:Recombinant Proteins; C490255:Reg3g protein, mouse; D051193:Toll-Like Receptors