TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis.
Mycobacterium tuberculosis (Mtb) signals through Toll-like receptor 2 (TLR2) to regulate antigen presenting cells (APCs). Mtb lipoproteins, including LpqH, LprA, LprG and PhoS1, are TLR2 agonists, but their co-receptor requirements are unknown. We studied Mtb lipoprotein-induced responses in TLR2(-/-), TLR1(-/-), TLR6(-/-), CD14(-/-) and CD36(-/-) macrophages. Responses to LprA, LprG, LpqH and PhoS1 were completely dependent on TLR2. LprG, LpqH, and PhoS1 were dependent on TLR1, but LprA did not require TLR1. None of the lipoproteins required TLR6, although a redundant contribution by TLR6 cannot be excluded. CD14 contributed to detection of LprA, LprG and LpqH, whereas CD36 contributed only to detection of LprA. Studies of lung APC subsets revealed lower TLR2 expression by CD11b(high)/CD11c(low) lung macrophages than CD11b(low)/CD11c(high) alveolar macrophages, which correlated with hyporesponsiveness of lung macrophages to LpqH. Thus, lung APC subsets differ in TLR expression, which may determine differences in responses to Mtb.
Department of Pathology, Case Western Reserve University School of Medicine/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Michael G
MG
Drage
Nicole D
ND
Pecora
Amy G
AG
Hise
Maria
M
Febbraio
Roy L
RL
Silverstein
Douglas T
DT
Golenbock
W Henry
WH
Boom
Clifford V
CV
Harding
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000942:Antigens, Bacterial; D018955:CD36 Antigens; D018950:Lipopolysaccharide Receptors; D008074:Lipoproteins; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6