| First Author | Okubo K | Year | 2021 |
| Journal | Cell Rep | Volume | 35 |
| Issue | 7 | Pages | 109142 |
| PubMed ID | 34010642 | Mgi Jnum | J:339733 |
| Mgi Id | MGI:6717041 | Doi | 10.1016/j.celrep.2021.109142 |
| Citation | Okubo K, et al. (2021) Inhibitory affinity modulation of FcgammaRIIA ligand binding by glycosphingolipids by inside-out signaling. Cell Rep 35(7):109142 |
| abstractText | The interaction of the human FcgammaRIIA with immune complexes (ICs) promotes neutrophil activation and thus must be tightly controlled to avoid damage to healthy tissue. Here, we demonstrate that a fungal-derived soluble beta-1,3/1,6-glucan binds to the glycosphingolipid long-chain lactosylceramide (LacCer) to reduce FcgammaRIIA-mediated recruitment to immobilized ICs under flow, a process requiring high-affinity FcgammaRIIA-immunoglobulin G (IgG) interactions. The inhibition requires Lyn phosphorylation of SHP-1 phosphatase and the FcgammaRIIA immunotyrosine-activating motif. beta-glucan reduces the effective 2D affinity of FcgammaRIIA for IgG via Lyn and SHP-1 and, in vivo, inhibits FcgammaRIIA-mediated neutrophil recruitment to intravascular IgG deposited in the kidney glomeruli in a glycosphingolipid- and Lyn-dependent manner. In contrast, beta-glucan did not affect FcgammaR functions that bypass FcgammaR affinity for IgG. In summary, we have identified a pathway for modulating the 2D affinity of FcgammaRIIA for ligand that relies on LacCer-Lyn-SHP-1-mediated inhibitory signaling triggered by beta-glucan, a previously described activator of innate immunity. |
