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.
Toll-like Receptors Induce a Phagocytic Gene Program through p38
Sean E. Doyle and Ryan M. O'Connell contributed equally to this work.
Abbreviations used in this paper: BMM, bone marrow–derived macrophage; DAPI, 6′-diamidino-2-phenylindole; ERK 1/2, extracellular signal–related kinase 1/2; FISH, fluorescence in situ hybridization; GFP, green fluorescence protein; ICAM-1, intercellular adhesion molecule-1; IRAK, IL-1 receptor–associated kinase; LOX-1, lectin-like oxidized LDL receptor; MARCO, macrophage scavenger receptor with collagenous structure; M-CSF, macrophage colony-stimulating factor; MOI, multiplicity of infection; MyD88, myeloid differentiation factor 88; NF, nuclear factor; PGN, peptidoglycan; poly I, polyinosinic acid; PRR, pattern recognition receptor; Q-PCR, quantitative realtime PCR; SR, scavenger receptor; SR-A, scavenger receptor-A; TLR, toll-like receptor; TRAF6, tumor necrosis factor receptor–associated factor 6.
Sean E. Doyle, Ryan M. O'Connell, Gustavo A. Miranda, Sagar A. Vaidya, Edward K. Chow, Philip T. Liu, Shinobu Suzuki, Nobutaka Suzuki, Robert L. Modlin, Wen-Chen Yeh, Timothy F. Lane, Genhong Cheng; Toll-like Receptors Induce a Phagocytic Gene Program through p38 . J Exp Med 5 January 2004; 199 (1): 81–90. doi: https://doi.org/10.1084/jem.20031237
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