Abstract
Guinea pig is a widely used animal for research and development of tuberculosis vaccines, since its pathological disease process is similar to that present in humans. We have previously reported that two C-type lectin receptors, Mincle (macrophage inducible C-type lectin, also called Clec4e) and MCL (macrophage C-type lectin, also called Clec4d), recognize the mycobacterial cord factor, trehalose-6,6′-dimycolate (TDM). Here, we characterized the function of the guinea pig homologue of Mincle (gpMincle) and MCL (gpMCL). gpMincle directly bound to TDM and transduced an activating signal through ITAM-bearing adaptor molecule, FcRγ. Whereas, gpMCL lacked C-terminus and failed to bind to TDM. mRNA expression of gpMincle was detected in the spleen, lymph nodes and peritoneal macrophages and it was strongly up-regulated upon stimulation of zymosan and TDM. The surface expression of gpMincle was detected on activated macrophages by a newly established monoclonal antibody that also possesses a blocking activity. This antibody potently suppressed TNF production in BCG-infected macrophages. Collectively, gpMincle is the TDM receptor in the guinea pig and TDM-Mincle axis is involved in host immune responses against mycobacteria.
Highlights
Tuberculosis is a life-threatening disease caused by the infection of Mycobacterium tuberculosis (M. tuberculosis) and related strains
We have previously reported that C-type lectin Mincle and MCL recognize TDM and transduce an activating signals through ITAM-bearing adaptor molecule, FcRc[6,7]
It has been reported that guinea pig macrophages can be activated by typical pathogen-associated molecular patterns (PAMPs) such as zymosan and TDM [19,20]
Summary
Tuberculosis is a life-threatening disease caused by the infection of Mycobacterium tuberculosis (M. tuberculosis) and related strains. M. bovis bacillus Calmette-Guerin (BCG) is the only available vaccine against tuberculosis, its effectiveness is still controversial for adults [1,2,3]. This has led to an urgent need for development of a new tuberculosis vaccine. It is necessary to understand the molecular mechanisms of recognition and activation of tuberculosis by the host immune system. Mincle is an essential receptor for TDM-induced innate immune responses such as granulomagenesis, and macrophage activation because these responses are almost completely abolished in Mincle-deficient mice [6,8]
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