Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA.
Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Cell Rep. 2021 May 18;35(7):109142. doi: 10.1016/j.celrep.2021.109142.
The interaction of the human FcγRIIA 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 β-1,3/1,6-glucan binds to the glycosphingolipid long-chain lactosylceramide (LacCer) to reduce FcγRIIA-mediated recruitment to immobilized ICs under flow, a process requiring high-affinity FcγRIIA-immunoglobulin G (IgG) interactions. The inhibition requires Lyn phosphorylation of SHP-1 phosphatase and the FcγRIIA immunotyrosine-activating motif. β-glucan reduces the effective 2D affinity of FcγRIIA for IgG via Lyn and SHP-1 and, in vivo, inhibits FcγRIIA-mediated neutrophil recruitment to intravascular IgG deposited in the kidney glomeruli in a glycosphingolipid- and Lyn-dependent manner. In contrast, β-glucan did not affect FcγR functions that bypass FcγR affinity for IgG. In summary, we have identified a pathway for modulating the 2D affinity of FcγRIIA for ligand that relies on LacCer-Lyn-SHP-1-mediated inhibitory signaling triggered by β-glucan, a previously described activator of innate immunity.
人类 FcγRIIA 与免疫复合物（ICs）的相互作用促进了中性粒细胞的激活，因此必须进行严格控制，以避免对健康组织造成损害。在这里，我们证明了一种真菌来源的可溶性β-1,3/1,6-葡聚糖与糖鞘脂长链乳糖基神经酰胺（LacCer）结合，以减少在流动条件下固定化 IC 上 FcγRIIA 介导的募集，这一过程需要高亲和力的 FcγRIIA-免疫球蛋白 G（IgG）相互作用。这种抑制作用需要 Lyn 对 SHP-1 磷酸酶的磷酸化和 FcγRIIA 的免疫酪氨酸激活基序。β-葡聚糖通过 Lyn 和 SHP-1 降低 FcγRIIA 对 IgG 的有效 2D 亲和力，并且在体内，以糖鞘脂和 Lyn 依赖性的方式抑制 FcγRIIA 介导的中性粒细胞募集到血管内 IgG 在肾脏肾小球中的沉积。相比之下，β-葡聚糖不影响绕过 FcγR 对 IgG 的亲和力的 FcγR 功能。总之，我们已经确定了一种调节 FcγRIIA 与配体 2D 亲和力的途径，该途径依赖于 LacCer-Lyn-SHP-1 介导的β-葡聚糖触发的抑制信号，β-葡聚糖是一种先前描述的先天免疫激活剂。
