Toll-like receptors induce a phagocytic gene program through p38.
Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program. Importantly, TLR-induced phagocytosis of bacteria was found to be reliant on myeloid differentiation factor 88-dependent signaling through interleukin-1 receptor-associated kinase-4 and p38 leading to the up-regulation of scavenger receptors. Interestingly, individual TLRs promote phagocytosis to varying degrees with TLR9 being the strongest and TLR3 being the weakest inducer of this process. We also demonstrate that TLR ligands not only amplify the percentage of phagocytes uptaking Escherichia coli, but also increase the number of bacteria phagocytosed by individual macrophages. Taken together, our data describe an evolutionarily conserved mechanism by which TLRs can specifically promote phagocytic clearance of bacteria during infection.
Doyle
Sean E
SE
Dept. of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, 8-240 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
O'Connell
Ryan M
RM
Miranda
Gustavo A
GA
Vaidya
Sagar A
SA
Chow
Edward K
EK
Liu
Philip T
PT
Suzuki
Shinobu
S
Suzuki
Nobutaka
N
Modlin
Robert L
RL
Yeh
Wen-Chen
WC
Lane
Timothy F
TF
Cheng
Genhong
G
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D017931:DNA Primers; D004926:Escherichia coli / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010587:Phagocytosis / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases
D017931:DNA Primers; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; C495371:TLR9 protein, human; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases