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

Abstract

BackgroundSystemic 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.ResultsWe 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 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.ConclusionThis novel pathway and regulation of IL-6 signaling by CEACAM1 defines a novel role for monocytes in the fever response of mice to LPS.Electronic supplementary materialThe online version of this article (10.1186/s12865-019-0287-y) contains supplementary material, which is available to authorized users.

Unaltered Fungal Burden and Lethality in Human CEACAM1-Transgenic Mice During Candida albicans Dissemination and Systemic Infection

“…Further, it is possible that mouse receptor orthologues of human interaction partners (e.g., mTLR2 and mTLR4) cannot interact with the human CEACAM1 receptor or that the human CEACAM1 transgenic mice simply lack the interaction partners necessary for C. albicans -specific CEACAM1-mediated responses. These interaction partners may be other immune receptors regulated by CEACAM1 in human cells (e.g., other CEACAM receptors, TLRs, lectins, or receptors of the integrin family) or adapter molecules and kinases/phosphatases necessary for the signal transduction (Müller et al, 2005; Skubitz and Skubitz, 2008; Slevogt et al, 2008; Muenzner et al, 2010, 2016; Lu et al, 2012; Singer et al, 2014; Schirbel et al, 2019; Zhang et al, 2019). However, the epithelial cells of the transgenic mice contain at least the necessary signaling molecules for a human CEACAM1-mediated alteration of the immune response to the bacterial pathogen Neisseria meningitidis (Johswich et al, 2013; Islam et al, 2018).…”

“…The highly conserved N-terminal variable Ig-like domain is recognized in a species-specific manner by bacterial, fungal, and viral pathogens (Gray-Owen and Blumberg, 2006; Klaile et al, 2017; Horst et al, 2018a; Helfrich and Singer, 2019). The synchronous engagement of CEACAM1 and other immune receptors, e.g., Toll-like receptors 2 and 4 (Slevogt et al, 2008; Lu et al, 2012; Singer et al, 2014; Schirbel et al, 2019; Zhang et al, 2019) or the inside-out activation of different integrin receptors (Müller et al, 2005; Skubitz and Skubitz, 2008; Muenzner et al, 2010, 2016), results in an altered regulation of the immune response that also depends on the cell type analyzed. Pathogen-CEACAM interactions and the resulting CEACAM1-mediated regulation of immune receptors are not restricted to immune cells but are an important factor in the bacterial colonization of mucosa with regard to the pathogen adherence and the downregulation of the immune response toward the pathogens (Muenzner et al, 2010; Johswich et al, 2013; Islam et al, 2018).…”

Biological characteristics of IL-6 and related intestinal diseases

“…With a wide variety of biological functions, IL-6 is the hub in mediating the communications among these cells and the cross-talk between intestinal epithelium and the gut microbiota. Not limited to the gastrointestinal tract, its receptor, IL-6R, is widely expressed, which causes inflammation in response to a wide variety of stimuli including infection, stress and trauma 3 , for example, in the liver leading to the acute phase protein response, in the hypothalamus together with IL-1β leading to systemic fever 4 , and in the gut leading to Th17 activation 5 . Within the scope of this review, we just limit it to the functions related to the intestine.…”

Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells

“…CEACAM1 could regulate LPS driven production of IL-6 and IL-1β, mediating the appearance of clinical phenomes, e.g. fever response, through the ITIM receptor [21].…”