Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.
Front Immunol. 2020 Aug 19;11:1793. doi: 10.3389/fimmu.2020.01793. eCollection 2020.
Inhibitory receptors are crucial immune regulators and are essential to prevent exacerbated responses, thus contributing to immune homeostasis. Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) is an immune inhibitory receptor which has collagen and collagen domain containing proteins as ligands. LAIR-1 is broadly expressed on immune cells and has a large availability of ligands in both circulation and tissues, implicating a need for tight regulation of this interaction. In the current study, we sought to examine the regulation and function of LAIR-1 on monocyte, dendritic cell (DC) and macrophage subtypes, using different models. We found that LAIR-1 is highly expressed on intermediate monocytes as well as on plasmacytoid DCs. LAIR-1 is also expressed on skin immune cells, mainly on tissue CD14 cells, macrophages and CD1c DCs. , monocyte and type-2 conventional DC stimulation leads to LAIR-1 upregulation, which may reflect the importance of LAIR-1 as negative regulator under inflammatory conditions. Indeed, we demonstrate that LAIR-1 ligation on monocytes inhibits toll like receptor (TLR)4 and Interferon (IFN)-α- induced signals. Furthermore, LAIR-1 is downregulated on GM-CSF and IFN-γ monocyte-derived macrophages and monocyte-derived DCs. In addition, LAIR-1 triggering during monocyte derived-DC differentiation results in significant phenotypic changes, as well as a different response to TLR4 and IFN-α stimulation. This indicates a role for LAIR-1 in skewing DC function, which impacts the cytokine expression profile of these cells. In conclusion, we demonstrate that LAIR-1 is consistently upregulated on monocytes and DC during the inflammatory phase of the immune response and tends to restore its expression during the resolution phase. Under inflammatory conditions, LAIR-1 has an inhibitory function, pointing toward to a potential intervention opportunity targeting LAIR-1 in inflammatory conditions.
抑制性受体是至关重要的免疫调节剂，对于防止过度反应至关重要，从而有助于免疫稳态。白细胞相关免疫球蛋白样受体 1（LAIR-1）是一种免疫抑制性受体，其配体为胶原蛋白和含有胶原蛋白结构域的蛋白质。LAIR-1在免疫细胞上广泛表达，在循环和组织中都有大量的配体，这意味着需要对这种相互作用进行严格的调节。在本研究中，我们试图使用不同的模型来研究 LAIR-1 在单核细胞、树突状细胞（DC）和巨噬细胞亚型上的调节和功能。我们发现 LAIR-1 在中间单核细胞和浆细胞样 DC 上高度表达。LAIR-1 也在皮肤免疫细胞上表达，主要在组织 CD14 细胞、巨噬细胞和 CD1c DC 上表达。在单核细胞和 2 型传统 DC 的刺激下，LAIR-1 的表达上调，这可能反映了 LAIR-1 在炎症条件下作为负调节剂的重要性。事实上，我们证明了单核细胞上 LAIR-1 的配体结合可抑制 Toll 样受体（TLR）4 和干扰素（IFN）-α诱导的信号。此外，GM-CSF 和 IFN-γ 诱导的单核细胞衍生巨噬细胞和单核细胞衍生 DC 上 LAIR-1 的表达下调。此外，在单核细胞衍生-DC 分化过程中触发 LAIR-1 会导致显著的表型变化，以及对 TLR4 和 IFN-α刺激的不同反应。这表明 LAIR-1 在偏倚 DC 功能方面发挥作用，从而影响这些细胞的细胞因子表达谱。总之，我们证明在免疫反应的炎症阶段，LAIR-1 在上皮细胞和 DC 上持续上调，并在缓解阶段趋于恢复其表达。在炎症条件下，LAIR-1 具有抑制作用，这表明在炎症条件下靶向 LAIR-1 可能具有潜在的干预机会。
