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. Author manuscript; available in PMC: 2017 Jan 1.
Published in final edited form as: Immunol Rev. 2016 Jan;269(1):212–227. doi: 10.1111/imr.12381

Figure 5. Potential model for regulation of TLR signaling by Lyp downstream of the TREM2/DAP12 inhibitory pathway.

Figure 5

Signaling through TREM2/DAP12 inhibits TLR responses through the DAP12 ITAM tyrosines, Syk and Btk/Tec. A) We hypothesize that the Lyp620R variant has the capacity to dephosphorylate Syk and/or the DAP12 ITAM tyrosines, resulting in partial phosphorylation of the DAP12 ITAM and/or Syk. This causes a reduction in the function of the TREM2/DAP12 inhibitory pathway in monocytes and macrophages, thereby moderating TLR-induced NF-kB-dependent inflammatory cytokine production. B) We propose that when Lyp activity is inhibited, there is increased phosphorylation of DAP12 or increased signaling through Syk, resulting in a stronger inhibitory signal through TREM2/DAP12 and reduced IL-6 and TNF secretion. C) We propose that Lyp620W has a greater capacity to dephosphorylate DAP12 or Syk. This results in reduced DAP12 or Syk phosphorylation and a weaker inhibitory signal through TREM2/DAP12, leading to increased IL-6 and TNF secretion. Alternatively, Lyp620W may dephosphorylate a unique, distinct inhibitor than Lyp620R, thereby promoting TLR-induced IL-6 and TNF secretion.

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