Fig. 3

SHIP1 regulates multiple receptors expressed in microglia and the microglial NLRP3 inflammasome. (A) TREM2 activation recruits p85 subunit of PI3K to the immunoreceptor tyrosine activating motif (ITAM) of DAP12. SHIP1 inhibits downstream activity of TREM2/DAP12 by binding to the immunoreceptor tyrosine activating motif (ITAM) of DAP12, preventing the association of p85 with DAP12, in osteoclasts. (B) SHIP1 inhibits the association of TLR4 with its adaptor protein MyD88 in macrophages. TLR4/MyD88 signaling leads to activation of NF-kB by inducing degradation of IΚB, which is also inhibited by SHIP1. (C) SHIP1 inhibits phagocytosis mediated by CR3 and FCγRIIA in macrophages. SHIP1 binds to the ITAM of FCγRIIA, inhibiting the downstream PI3K signaling. SHIP1 can also bind to the immunoreceptor tyrosine inhibitory motif (ITIM) of the inhibitory receptor FCγRIIB, which enhances FCγRIIB-mediated inhibition of phagocytosis. The exact mechanism of how SHIP1 inhibits CR3 is currently unknown. (D) SHIP1 inhibits the activation of the NLRP3 inflammasome. Pharmacological inhibition of SHIP1 or genetic reduction of INPP5D activates the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs), resulting in increased secretion of IL-1β and IL-18. On the other hand, loss of SHIP1 inhibits the upregulation of pro-IL-1β, suggesting that reduction of SHIP1 activity may induce inflammasome activation while inhibiting the priming step in some contexts. ECS, extracellular space. Figure created in BioRender.com [114, 121, 137, 138, 161, 197]