MyD88 and Type I interferon receptor-mediated chemokine induction and monocyte recruitment during Listeria monocytogenes infection.
Monocytes play a central role in defense against infection, but the mechanisms promoting monocyte recruitment and activation remain incompletely defined. Defense against Listeria monocytogenes, an intracellular bacterial pathogen, requires in vivo MCP-1 induction and CCR2-dependent recruitment of Ly6C(high) monocytes from bone marrow to sites of infection. Herein, we demonstrate that infection of bone marrow-derived macrophages with virulent L. monocytogenes induces MCP-1 expression in two phases. The first phase is rapid, induces low-level production of MCP-1, and is dependent on TLR/MyD88 signaling. The second phase promotes prolonged, higher level MCP-1 secretion and is dependent on signaling via the type I IFN receptor (IFNAR). Although attenuated L. monocytogenes strains that remain confined to the phagosome trigger TLR/MyD88-mediated signals and induce low-level MCP-1 expression, only cytosol-invasive bacteria promote IFNAR-dependent MCP-1 expression. In vivo, deficiency of either MyD88 or IFNAR signaling does not impair early monocyte emigration from bone marrow and recruitment to infected spleen. Loss of both MyD88 and IFNAR-mediated MCP-1 induction, however, results in deficient Ly6C(high) monocyte recruitment and increased susceptibility to L. monocytogenes infection. Our studies demonstrate that distinct but partially overlapping signal transduction pathways provide redundancy that ensures optimal monocyte recruitment to sites of microbial infection.
Jia
Ting
T
Infectious Diseases Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Leiner
Ingrid
I
Dorothee
Guillaume
G
Brandl
Katharina
K
Pamer
Eric G
EG
D000818:Animals; D001854:Bone Marrow Cells; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D018925:Chemokines / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte; D003600:Cytosol / Q000382:microbiology; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology*; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000502:physiology*; D053633:Receptor, Interferon alpha-beta / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000382:microbiology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta