Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1.
Mycobacterium abscessus (Mab) is an emerging and rapidly growing non-tuberculous mycobacterium (NTM). Compared with M. tuberculosis, which is responsible for tuberculosis, much less is known about NTM-induced innate immune mechanisms. Here we investigated the involvement of pattern-recognition receptors and associated signalling in Mab-mediated innate immune responses. Mab activated the extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinases (MAPKs), and induced the secretion of tumour necrosis factor-alpha, interleukin (IL)-6 and IL-12p40 in murine macrophages via Toll-like receptor (TLR) 2. Notably, the activation of ERK1/2, but not p38, was crucial for Mab-induced pro-inflammatory cytokine production. The ITAM-like motif of dectin-1 critically contributed to Mab internalization and cytokine secretion by macrophages. In addition, dectin-1, in cooperation with TLR2, was required for the efficient phagocytosis of Mab, ERK1/2 activation and pro-inflammatory cytokine secretion. Co-immunoprecipitation and confocal analysis showed the physical interaction and colocalization of dectin-1 with TLR2 following Mab stimulation. Moreover, dectin-1-induced Syk activation was essential for the production of inflammatory cytokines and the release of reactive oxygen species by Mab-infected macrophages. Collectively, these data demonstrate that Mab actively internalizes into and robustly activates innate immune responses in macrophages through a physical and functional interaction between TLR2 and dectin-1.
Shin
Dong-Min
DM
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301-747, Korea.
Yang
Chul-Su
CS
Yuk
Jae-Min
JM
Lee
Ji-Yeon
JY
Kim
Ki Hye
KH
Shin
Sung Jae
SJ
Takahara
Kazuhiko
K
Lee
Sung Joong
SJ
Jo
Eun-Kyeong
EK
D000818:Animals; D016207:Cytokines / Q000276:immunology; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009161:Mycobacterium / Q000276:immunology*; D009164:Mycobacterium Infections / Q000276:immunology* / Q000382:microbiology; D009419:Nerve Tissue Proteins / Q000276:immunology*; D010587:Phagocytosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D000099181:Dectin-1
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D000099181:Dectin-1; C000606897:Syk protein, mouse