Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1000474
Title: MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis
Authors: Bowdish D.M.E.
Sakamoto K.
Kim M.-J.
Kroos M.
Mukhopadhyay S.
Leifer C.A.
Tryggvason K. 
Gordon S.
Russell D.G.
Keywords: CD14 antigen
cord factor
immunoglobulin enhancer binding protein
interleukin 1beta
interleukin 6
marco receptor
mitogen activated protein kinase
mitogen activated protein kinase 1
mitogen activated protein kinase 3
myeloid differentiation factor 88
protein MD 2
scavenger receptor A
toll like receptor 2
toll like receptor 4
tumor necrosis factor alpha
unclassified drug
CD14 antigen
cytokine
immunoglobulin receptor
MARCO protein, human
Marco protein, mouse
microsphere
scavenger receptor A
TLR2 protein, human
TLR4 protein, human
toll like receptor 2
animal cell
animal experiment
article
controlled study
cytokine production
enzyme activation
enzyme phosphorylation
human
human cell
mouse
Mycobacterium tuberculosis
nonhuman
peritoneum macrophage
phagosome
protein expression
protein localization
receptor binding
signal transduction
animal
C57BL mouse
CHO cell
Cricetulus
cytoplasm
fluorescence microscopy
genetics
hamster
immunology
macrophage
metabolism
Mycobacterium tuberculosis
Mus
Mycobacterium tuberculosis
Animals
Antigens, CD14
CHO Cells
Cord Factors
Cricetinae
Cricetulus
Cytokines
Cytoplasm
Humans
Macrophages
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Microspheres
Mycobacterium tuberculosis
Phagosomes
Receptors, Immunologic
Scavenger Receptors, Class A
Signal Transduction
Toll-Like Receptor 2
Toll-Like Receptor 4
Issue Date: 2009
Citation: Bowdish D.M.E., Sakamoto K., Kim M.-J., Kroos M., Mukhopadhyay S., Leifer C.A., Tryggvason K., Gordon S., Russell D.G. (2009). MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis. PLoS Pathogens 5 (6) : e1000474. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1000474
Rights: Attribution 4.0 International
Abstract: Virtually all of the elements of Mycobacterium tuberculosis (Mtb) pathogenesis, including pro-inflammatory cytokine production, granuloma formation, cachexia, and mortality, can be induced by its predominant cell wall glycolipid, trehalose 6,6?-dimycolate (TDM/cord factor). TDM mediates these potent inflammatory responses via interactions with macrophages both in vitro and in vivo in a myeloid differentiation factor 88 (MyD88)-dependent manner via phosphorylation of the mitogen activated protein kinases (MAPKs), implying involvement of toll-like receptors (TLRs). However, specific TLRs or binding receptors for TDM have yet to be identified. Herein, we demonstrate that the macrophage receptor with collagenous structure (MARCO), a class A scavenger receptor, is utilized preferentially to "tether" TDM to the macrophage and to activate the TLR2 signaling pathway. TDM-induced signaling, as measured by a nuclear factor-kappa B (NF-?B)-luciferase reporter assay, required MARCO in addition to TLR2 and CD14. MARCO was used preferentially over the highly homologous scavenger receptor class A (SRA), which required TLR2 and TLR4, as well as their respective accessory molecules, in order for a slight increase in NF-?B signaling to occur. Consistent with these observations, macrophages from MARCO-/- or MARCO-/-SRA-/- mice are defective in activation of extracellular signal-related kinase 1/2 (ERK1/2) and subsequent pro-inflammatory cytokine production in response to TDM. These results show that MARCO-expressing macrophages secrete pro-inflammatory cytokines in response to TDM by cooperation between MARCO and TLR2/CD14, whereas other macrophage subtypes (e.g. bone marrow-derived) may rely somewhat less effectively on SRA, TLR2/CD14, and TLR4/MD2. Macrophages from MARCO -/- mice also produce markedly lower levels of pro-inflammatory cytokines in response to infection with virulent Mtb. These observations identify the scavenger receptors as essential binding receptors for TDM, explain the differential response to TDM of various macrophage populations, which differ in their expression of the scavenger receptors, and identify MARCO as a novel component required for TLR signaling. © 2009 Bowdish et al.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/161674
ISSN: 15537366
DOI: 10.1371/journal.ppat.1000474
Rights: Attribution 4.0 International
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