Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, 1500E Duarte Road, Duarte, CA91010, USA.
BMC Immunol. 2019 Jan 23;20(1):7. doi: 10.1186/s12865-019-0287-y.
Systemic inflammation and the fever response to pathogens are coordinately regulated by IL-6 and IL-1β. We previously showed that CEACAM1 regulates the LPS driven expression of IL-1β in murine neutrophils through its ITIM receptor.
We now show that the prompt secretion of IL-6 in response to LPS is regulated by CEACAM1 expression on bone marrow monocytes. Ceacam1 mice over-produce IL-6 in response to an i.p. LPS challenge, resulting in prolonged surface temperature depression and overt diarrhea compared to their wild type counterparts. Intraperitoneal injection of a Cu-labeled LPS, PET imaging agent shows confined localization to the peritoneal cavity, and fluorescent labeled LPS is taken up by myeloid splenocytes and muscle endothelial cells. While bone marrow monocytes and their progenitors (CD11bLy6G) express IL-6 in the early response (< 2 h) to LPS in vitro, these cells are not detected in the bone marrow after in vivo LPS treatment perhaps due to their rapid and complete mobilization to the periphery. Notably, tissue macrophages are not involved in the early IL-6 response to LPS. In contrast to human monocytes, TLR4 is not expressed on murine bone marrow monocytes. Instead, the alternative LPS receptor RP105 is expressed and recruits MD1, CD14, Src, VAV1 and β-actin in response to LPS. CEACAM1 negatively regulates RP105 signaling in monocytes by recruitment of SHP-1, resulting in the sequestration of pVAV1 and β-actin from RP105.
This novel pathway and regulation of IL-6 signaling by CEACAM1 defines a novel role for monocytes in the fever response of mice to LPS.
系统性炎症和对病原体的发热反应是由 IL-6 和 IL-1β 协同调节的。我们之前表明，CEACAM1 通过其 ITIM 受体调节 LPS 驱动的小鼠中性粒细胞中 IL-1β 的表达。
我们现在表明，CEACAM1 表达在骨髓单核细胞上调节 LPS 反应中 IL-6 的迅速分泌。与野生型相比，Ceacam1 小鼠在腹腔内 LPS 挑战时过度产生 IL-6，导致表面温度下降持续时间延长，并有明显腹泻。用 Cu 标记的 LPS（PET 成像剂）腹腔内注射显示局限于腹腔的定位，荧光标记的 LPS 被髓样脾细胞和肌肉内皮细胞摄取。虽然骨髓单核细胞及其前体（CD11bLy6G）在体外对 LPS 的早期反应（<2 小时）中表达 IL-6，但这些细胞在体内 LPS 处理后不在骨髓中检测到，可能是由于它们迅速而完全地动员到外周。值得注意的是，组织巨噬细胞不参与 LPS 对早期 IL-6 的反应。与人类单核细胞不同，TLR4 不在小鼠骨髓单核细胞上表达。相反，替代 LPS 受体 RP105 表达，并在 LPS 反应中招募 MD1、CD14、Src、VAV1 和 β-肌动蛋白。CEACAM1 通过募集 SHP-1 负调节单核细胞中的 RP105 信号传导，从而将 pVAV1 和 β-肌动蛋白从 RP105 中隔离出来。
CEACAM1 对 IL-6 信号的这种新途径和调节定义了单核细胞在小鼠对 LPS 的发热反应中的新作用。
