Mincle suppresses toll-like receptor 4 activation

Stephanie H. Greco, Syed Kashif Mahmood, Anne Kristin Vahle, Atsuo Ochi, Jennifer Batel, Michael Deutsch, Rocky Barilla, Lena Seifert, H. Leon Pachter, Donnele Daley, Alejandro Torres-Hernandez, Mautin Hundeyin, Vishnu R. Mani, George Miller

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Abstract

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation.We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4–mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not upregulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle-/- leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation.

Original languageEnglish (US)
Pages (from-to)185-194
Number of pages10
JournalJournal of Leukocyte Biology
Volume100
Issue number1
DOIs
StatePublished - Jul 2016

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

Greco, S. H., Mahmood, S. K., Vahle, A. K., Ochi, A., Batel, J., Deutsch, M., Barilla, R., Seifert, L., Leon Pachter, H., Daley, D., Torres-Hernandez, A., Hundeyin, M., Mani, V. R., & Miller, G. (2016). Mincle suppresses toll-like receptor 4 activation. Journal of Leukocyte Biology, 100(1), 185-194. https://doi.org/10.1189/jlb.3A0515-185R