Rhamnose alleviates the proinflammatory response during endotoxemia via the CEACAM1/LGALS9-p38 axis

Abstract

Gut microbiota plays an important role in orchestrating the host immune response. We previously reported that gut microbiota-derived rhamnose enhances the phagocytosis of macrophages, upon which we further asked whether rhamnose has modulatory effects on inflammation. Here, we show that, in an LPS-induced endotoxic mouse model, plasma rhamnose levels are increased. This bacteria-derived sugar alone does not impact inflammatory cytokine homeostasis or cause organ damage. In contrast, it is able to alleviate endotoxin-induced systemic inflammation and organ damage. Mechanistically, in macrophages in vitro, rhamnose binds to the V39, D40, and T101 sites of carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1), subsequently promoting the interaction between CEACAM1 and galectin 9 (LGALS9), which increases the protein level of dual-specificity protein phosphatase 1 (DUSP1). This inhibits p38 phosphorylation and thus attenuates the LPS-triggered expressions of proinflammatory factors. Collectively, our results suggest that rhamnose signals via the CEACAM1/LGALS9-p38 axis, which suppresses endotoxemia-associated inflammation, and that rhamnose is a candidate anti-inflammatory agent for the control of infection-induced organ damage.

1. Introduction

The infection-induced host uncontrolled inflammatory response and consequent cytokine overproduction are the key drivers of organ damage and failure development [1,2]. For example, during the onset of sepsis, innate immune cells such as macrophages are overactivated by pathogen-associated molecular patterns (PAMPs) and secrete large amounts of cytokines to generate a “cytokine storm”. These inflammatory factors can damage healthy cells and ultimately cause organ dysfunction and failure [3–7]. The intracellular signaling pathways that mediate cytokine production are well known. PAMPs are recognized by pattern recognition receptors (PRRs) in immune cells, triggering downstream signaling cascades [8,9]. Mitogen-activated protein kinase (MAPK) signaling is a well-established proinflammatory pathway, and blocking MAPK activity has been demonstrated to decrease inflammation in various disease contexts [10–12]. Thus, uncovering the upstream regulatory mechanisms of MAPK may provide insights into new pharmacological targets for inflammatory disease therapy.

The gut microbiota has been demonstrated to closely modulate host inflammation [13–15]. On the one hand, bacteria-derived harmful products such as LPS and bacterial DNA could be recognized as PAMPs and directly elicit proinflammatory responses [9,16]. LPS, also referred to as endotoxin, is the most widely used challenge approach to induce infectious inflammation in basic research [17]. On the other hand, it is also evident that the gut microbiota generates various anti-inflammatory compounds, such as short-chain fatty acids and certain secondary bile acids [18–21]. Thus, the detailed role played by the gut microbiota during inflammation progression is complex, and more anti-inflammatory elements need to be explored.