CEACAM1 regulates the IL-6 mediated fever response to LPS through the RP105 receptor in murine monocytes

Abstract

Systemic inflammation and the fever response to pathogens are coordinately regulated by IL-6 and IL-1{beta}. We previously showed that CEACAM1 regulates the LPS driven expression of IL-1{beta} 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 64Cu-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 (CD11b+Ly6G-) express IL-6 in the early response (<2 hours) to LPS in vitro, these cells are not detected in the bone marrow after in vivo LPS treatment 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 {beta}-actin in response to LPS to produce IL-6. CEACAM1 negatively regulates RP105 signaling in monocytes by recruitment of SHP-1, resulting in the sequestration of pVAV1 and {beta}-actin from RP105. This novel pathway and regulation of IL-6 producing by CEACAM1 defines a novel role for monocytes in the fever of mice to LPS.\n\nAUTHOR SUMMARYFever is one of the most common signs of the immune response to pathogens. The fever response to LPS or endotoxin of gram-negative bacteria is mediated by the combined action of two cytokines, IL-1{beta} and IL-6. Regulation of their production in response to LPS is an important area of investigation. While we previously showed that the regulation of IL-1{beta} production in neutrophils is through the lymphocyte receptor CEACAM1, we were interested if a similar mechanism operated for IL-6. Using a mouse model in which the CEACAM1 gene was knocked out, we show that IL-6 is over-produced compared to normal mice, and that monocytes, rather than neutrophils were the principal IL-6 producing cells. Surprisingly, murine monocytes do not express TLR4, the most commonly studied receptor for LPS, but instead express the low affinity LPS receptor, RP105, a receptor common expressed on B-cells. Furthermore, we show that bone marrow monocytes are rapidly released into the blood and home to tissues throughout the body in response to LPS. These findings explain much of the confusion in the literature concerning the immediate source of IL-6 and the distinct differences between murine and human monocytes in their in responses to LPS.