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Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution.

Lee WB, Kang JS, Choi WY, Zhang Q, Kim CH, Choi UY, Kim-Ha J, Kim YJ - Nat Commun (2016)

Bottom Line: Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production.In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution.Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

ABSTRACT
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

No MeSH data available.


Related in: MedlinePlus

TDM-induced nitric oxide upregulation inhibits activation of the NLRP3 inflammasome.(a) WT and Mincle−/− BMDMs were stimulated with LPS (L+A) or co-stimulated with LPS and TDM (L+T+A) for 12 h in the presence of the indicated chemical inhibitors, and then treated with ATP for 1 h. ELISA of released IL-1β. (b) Immunoblot analysis of total S-nitrosylated proteins (biotin), NLRP3 or caspase-1 in BMDMs treated with LPS or stimulated with TDM for 12 h. Below (lysate), immunoblot analysis of total lysate fractions. (c) Immunoblot analysis of IL-1β and caspase-1 from LPS-treated WT and iNOS−/− BMDMs, stimulated with TDM for 12 h, and then treated with ATP for 1 h or nigericin for 3 h. Data are representative of one (a) or two (b,c) independent experiments.
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f2: TDM-induced nitric oxide upregulation inhibits activation of the NLRP3 inflammasome.(a) WT and Mincle−/− BMDMs were stimulated with LPS (L+A) or co-stimulated with LPS and TDM (L+T+A) for 12 h in the presence of the indicated chemical inhibitors, and then treated with ATP for 1 h. ELISA of released IL-1β. (b) Immunoblot analysis of total S-nitrosylated proteins (biotin), NLRP3 or caspase-1 in BMDMs treated with LPS or stimulated with TDM for 12 h. Below (lysate), immunoblot analysis of total lysate fractions. (c) Immunoblot analysis of IL-1β and caspase-1 from LPS-treated WT and iNOS−/− BMDMs, stimulated with TDM for 12 h, and then treated with ATP for 1 h or nigericin for 3 h. Data are representative of one (a) or two (b,c) independent experiments.

Mentions: To define the pathways involved in Mincle-mediated IL-1β suppression, we inhibited diverse signalling molecules with specific chemical inhibitors, and examined their effects on IL-1β production with Mincle activation (Fig. 2a). As expected from previous studies regarding the requirement of Src and Syk kinases for Mincle signalling1617, inhibitors of Src (Srci) and Syk (Syki) effectively prevented the inhibitory effect of Mincle on IL-1β secretion (Fig. 2a). In addition, inducible nitric oxide synthase (iNOS) inhibitors (1400W and L-NMMA) strongly inhibited Mincle-mediated downregulation of IL-1β secretion, indicating NO as a mediator of IL-1β inhibition by Mincle (Fig. 2a). These inhibitors did not affect other immune signalling pathways leading to proIL-1β (and proCaspase-1) production (Supplementary Fig. 5a).


Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution.

Lee WB, Kang JS, Choi WY, Zhang Q, Kim CH, Choi UY, Kim-Ha J, Kim YJ - Nat Commun (2016)

TDM-induced nitric oxide upregulation inhibits activation of the NLRP3 inflammasome.(a) WT and Mincle−/− BMDMs were stimulated with LPS (L+A) or co-stimulated with LPS and TDM (L+T+A) for 12 h in the presence of the indicated chemical inhibitors, and then treated with ATP for 1 h. ELISA of released IL-1β. (b) Immunoblot analysis of total S-nitrosylated proteins (biotin), NLRP3 or caspase-1 in BMDMs treated with LPS or stimulated with TDM for 12 h. Below (lysate), immunoblot analysis of total lysate fractions. (c) Immunoblot analysis of IL-1β and caspase-1 from LPS-treated WT and iNOS−/− BMDMs, stimulated with TDM for 12 h, and then treated with ATP for 1 h or nigericin for 3 h. Data are representative of one (a) or two (b,c) independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837483&req=5

f2: TDM-induced nitric oxide upregulation inhibits activation of the NLRP3 inflammasome.(a) WT and Mincle−/− BMDMs were stimulated with LPS (L+A) or co-stimulated with LPS and TDM (L+T+A) for 12 h in the presence of the indicated chemical inhibitors, and then treated with ATP for 1 h. ELISA of released IL-1β. (b) Immunoblot analysis of total S-nitrosylated proteins (biotin), NLRP3 or caspase-1 in BMDMs treated with LPS or stimulated with TDM for 12 h. Below (lysate), immunoblot analysis of total lysate fractions. (c) Immunoblot analysis of IL-1β and caspase-1 from LPS-treated WT and iNOS−/− BMDMs, stimulated with TDM for 12 h, and then treated with ATP for 1 h or nigericin for 3 h. Data are representative of one (a) or two (b,c) independent experiments.
Mentions: To define the pathways involved in Mincle-mediated IL-1β suppression, we inhibited diverse signalling molecules with specific chemical inhibitors, and examined their effects on IL-1β production with Mincle activation (Fig. 2a). As expected from previous studies regarding the requirement of Src and Syk kinases for Mincle signalling1617, inhibitors of Src (Srci) and Syk (Syki) effectively prevented the inhibitory effect of Mincle on IL-1β secretion (Fig. 2a). In addition, inducible nitric oxide synthase (iNOS) inhibitors (1400W and L-NMMA) strongly inhibited Mincle-mediated downregulation of IL-1β secretion, indicating NO as a mediator of IL-1β inhibition by Mincle (Fig. 2a). These inhibitors did not affect other immune signalling pathways leading to proIL-1β (and proCaspase-1) production (Supplementary Fig. 5a).

Bottom Line: Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production.In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution.Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

ABSTRACT
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

No MeSH data available.


Related in: MedlinePlus