Critical roles of CX3CR1+ mononuclear phagocytes in maintaining gut‐liver axis health

Emerging evidence underscores the importance of the gut-liver axis in the pathogenesis of nonalcoholic fatty liver disease. A key role in the maintenance of gut-liver axis health has been attributed to intestinal microbiota. Intestinal dysbiosis disrupts intestinal barrier integrity, which facilitates intestinal leakiness and translocation of intestinal-derived bacteria or bacterial products to the liver. These foreign antigens trigger an inflammatory response that contributes to the development and progression of steatohepatitis. The intestinal immune system recognizes antigens specifically and compartmentalizes intestinal immune response to avoid inflammation. Key participants in intestinal innate immunity are intestinal mononuclear phagocytes (MNPs), which comprise dendritic cells (DCs) and macrophages (Mus). MNPs not only kill pathogens directly, but also present antigens to immune effector cells, which elicit innate and adaptive immune responses that limit microbial translocation to the portal vein. MNPs can be subdivided based on expression of CD103 or CX3CR1, whereas CX3CR1 MNPs migrate to draining lymph nodes and initiate immune responses under conditions of dysbiosis. Schneider et al. recently recognized the central role of CX3CR1 in microbiota-mediated activation of innate immune responses, which participated in the procession of diet-induced steatohepatitis. Using Cx3cr1-deficient mice, they concluded that CX3CR1 signaling was crucial in maintaining intestinal barrier integrity. Lack of Cx3cr1 expression was associated with reduced numbers of intestinal Mus and increased bacterial translocation. It is noteworthy that the roles of CX3CR1MHCII CD11bCD11cF4/80 Mus were determined in their study whereas CX3CR1MHCIICD11b CD11cF4/80 DCs were not evaluated. CX3CR1 DCs are also key regulators of intestinal immune homeostasis and inflammation as Mus. CX3CR1 DCs are on the front line in maintaining intestinal integrity, which can form transepithelial dendrites to phagocytose luminal pathogenic bacteria directly. CX3CR1 DCs display poor T-cell stimulatory capacity under steady-state conditions while they shuttle harmful pathogens to mesenteric lymph nodes in the case of dysbiosis, where they trigger specific immune response through a MyD88dependent signaling pathway. Niess et al. suggested that CX3CR1-dependent processes, which controlled host interactions of specialized DCs with commensal and pathogenic bacteria, might regulate immunological tolerance and inflammation. It was recently reported that CX3CR1 DCs could up-regulate CCR7 and migrate to secondary lymphoid organs, suggesting a broader role in orchestrating immunity. Therefore, CX3CR1 DCs are essential for both induction of active immunity and maintenance of barrier homeostasis. Despite phagocytosing bacteria or presenting antigens to immune effector cells similar to Mus, CX3CR1 1 DCs may play different roles in recognizing and responding to different microorganisms by producing distinct patterns of inflammatory cytokines. CX3CR1 DCs may participate in maintaining intestinal integrity alone or in combination with Mus to limit bacterial translocation to the liver by multiple mechanisms. Their specific functions can be studied in vivo by generating novel mouse strains, allowing depletion of each cell population. Without a thorough understanding of the activities of CX3CR1 DCs within the intestinal immune system, it is not possible to decipher the role of CX3CR1 in the maintenance of gut-liver axis health. The incomplete evidence might lead to unreliable conclusions. Because the specific roles of CX3CR1 DCs were not examined in their study, can the authors explain the validity of their conclusions in the absence of studying such DCs?