Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways.
Neutrophils are the first immune cells to migrate into infected tissue sites. Therefore an important step in the initiation of an immune response is the synthesis of the neutrophil-recruiting chemokines. In this in vivo study in mice, we show that resident tissue macrophages are the source of the major neutrophil chemoattractants, KC and MIP-2. Synthesis of these chemokines is rapidly regulated at the transcriptional level by signaling through TLR2, TLR3, and TLR4 that have diverse specificities for pathogens. The major and alternative TLR signaling pathways are characterized by the adaptor proteins MyD88 or TRIF, respectively. KC and MIP-2 are both produced by signaling through MyD88. However MIP-2, but not KC, is also synthesized through the TRIF adaptor protein, identifying it as a new product of this alternative pathway. Use of both pathways by TLR4 ensures maximal levels of KC and MIP-2 that lead to robust neutrophil recruitment. However the MIP-2 generated exclusively by the TRIF pathway is still sufficient to cause an influx of neutrophils. In summary we show that TLR signaling by tissue macrophages directly controls the synthesis of neutrophil-attracting chemokines that are essential for the earliest recruitment step in the innate immune response to microbial challenge.
De Filippo
Katia
K
Leukocyte Adhesion Laboratory, Cancer Research United Kingdom, London Research Institute, London, United Kingdom.
Henderson
Robert B
RB
Laschinger
Melanie
M
Hogg
Nancy
N
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000235:genetics; D054426:Chemokine CXCL2 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000502:physiology*
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors