Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Center for Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Sci Rep. 2017 Mar 21;7(1):270. doi: 10.1038/s41598-017-00290-w.
C1q collagen-like region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-complement mechanism for maintaining immune quiescence. Given the binding promiscuity of C1q's globular region (gC1q), we hypothesized that C1q concurrently associates with distinct inhibitory immunoreceptors to produce C1q-mediated modulatory networking. Like LAIR-1, CD33 inhibitory immunoreceptors are highly expressed on monocytes. Binding CD33 restricts cell activation/differentiation; however, natural ligands for CD33 remain elusive. CD33 has IgC2-like domains potentially recognized by gC1q. Thus, we asked whether C1q binds to CD33 and if C1q mediates CD33/LAIR-1 crosslinking. Our findings demonstrate that C1q and gC1q interact with CD33 to activate its inhibitory motifs, while CLR does not. Whole C1q is required to crosslink CD33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory motifs. While C1q binds CD33C2 domains, decreased C1q-CD33 interactions resulting from sialic acid masking of CD33C2 domains suggests a process for regulating C1q-CD33 activity. Consistent with defective self-tolerance, CD33/LAIR-1 expression is reduced in systemic lupus erythematosus (SLE) myelomonocytes. The anti-inflammatory cytokine M-CSF, but not DC growth factors, sustains CD33/LAIR-1 expression on both healthy and SLE cells suggesting further biological control of C1q-CD33/LAIR-1 processes.
C1q 胶原样区域 (CLR) 与 LAIR-1 抑制性免疫受体结合并激活该受体，代表了维持免疫静止的非补体机制。鉴于 C1q 球状区域 (gC1q) 的结合多态性，我们假设 C1q 同时与不同的抑制性免疫受体结合，以产生 C1q 介导的调节网络。与 LAIR-1 一样，CD33 抑制性免疫受体在单核细胞上高度表达。结合 CD33 限制细胞激活/分化；然而，CD33 的天然配体仍然难以捉摸。CD33 具有潜在可被 gC1q 识别的 IgC2 样结构域。因此，我们询问 C1q 是否与 CD33 结合，以及 C1q 是否介导 CD33/LAIR-1 交联。我们的研究结果表明，C1q 和 gC1q 与 CD33 相互作用以激活其抑制基序，而 CLR 则不会。需要完整的 C1q 来交联 CD33 和 LAIR-1，并同时激活 CD33/LAIR-1 抑制基序。虽然 C1q 结合 CD33C2 结构域，但由于唾液酸化掩蔽 CD33C2 结构域导致 C1q-CD33 相互作用减少，表明存在调节 C1q-CD33 活性的过程。与自身耐受缺陷一致，系统性红斑狼疮 (SLE) 骨髓单核细胞中 CD33/LAIR-1 的表达减少。抗炎细胞因子 M-CSF，但不是 DC 生长因子，维持健康细胞和 SLE 细胞上的 CD33/LAIR-1 表达，表明对 C1q-CD33/LAIR-1 过程的进一步生物学控制。
