Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction.
The contribution of Toll-like receptors (TLRs) to phagocytosis of Borrelia burgdorferi has not been extensively studied. We show that bone marrow-derived macrophages (BMDM) from MyD88(-/-) mice or Raw cells transfected with a dominant-negative MyD88 were unable to efficiently internalize B. burgdorferi. Knockouts of TLR2 and TLR9 or knockdown of TLR5 by small interfering RNA produced no defects in phagocytosis of B. burgdorferi. Production of inflammatory cytokines was greatly diminished in MyD88(-/-) BMDM but only partially affected in TLR2(-/-) BMDM or knockdown of TLR5 and unaffected in TLR9(-/-) BMDM. Cytochalasin D reduced cytokine induction, but not to the level of the MyD88(-/-) BMDM. Addition of cytochalasin D to TLR2(-/-) BMDM inhibited inflammatory responses to B. burgdorferi to the level of MyD88(-/-) BMDM, consistent with a role for TLR2 in both recognition of extracellular products and lysosomal sampling by TLR2 after processing of the organism. Cytochalasin D had no impact on cytokine production in cells undergoing TLR5 knockdown. These results suggest that MyD88, but not TLR2, TLR5, and TLR9, is important for the uptake of B. burgdorferi and that MyD88 affects inflammatory responses through both its effects on phagocytosis and its role in transducing signals from TLR2 and TLR5.
Shin
Ok S
OS
Department of Pathology/Immunology, Sackler School for Graduate Biomedical Studies, Tufts University, 155 Harrison Avenue, Boston, Massachusetts 02111, USA.
Isberg
Ralph R
RR
Akira
Shizuo
S
Uematsu
Satoshi
S
Behera
Aruna K
AK
Hu
Linden T
LT
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D025065:Borrelia burgdorferi / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010587:Phagocytosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001426:Bacterial Proteins; D016207:Cytokines; D008074:Lipoproteins; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D048051:p38 Mitogen-Activated Protein Kinases