Novel macrophage mediated signals regulate the immunoregulatory environment of the neonatal liver - Project Summary The balance between regulatory and immunogenic immune responses is critical for liver homeostasis during perinatal life because dysregulation of either can lead to chronic viral infection from sustained immune suppression (as in chronic neonatal hepatitis B) or, to neonatal cirrhosis from unmitigated inflammation (as in biliary atresia). It is therefore essential to understand the mechanisms that maintain the delicate balance between regulatory immune responses and immunity in the perinatal liver as devastating sequelae of either too much immune suppression, in the case of chronic neonatal hepatitis B, or too much immunity, in the case of biliary atresia, leads to significant morbidity. In this proposal, we will investigate the role of the scavenger receptor MARCO in maintaining this crucial balance between regulation and immunity in the perinatal liver. Scavenger receptors are cell surface receptors found on phagocytic immune cells, and are important mediators of immune homeostasis, inflammation, and tolerance. We have identified an important role for the class A scavenger receptor MARCO expressed on macrophages in tuning immunoregulatory responses and inflammation in the perinatal liver. Our preliminary data indicates that MARCO is highly expressed on mouse and human liver macrophages, restricts anti-inflammatory myeloid cells, and worsens outcomes in a mouse model of perinatal liver inflammation. Our data also support the idea that MARCO restricts anti-inflammatory functions of macrophages by limiting responsiveness to the potent anti-inflammatory cytokine interleukin-10 (IL-10). We therefore hypothesize that MARCO restricts regulatory/anti-inflammatory immune responses by inhibiting responsiveness to IL-10. To address this hypothesis, we will use novel tools that involve technically challenging portal vein injections of a model antigen to quantify endogenous antigen-specific immune responses in neonatal liver and a CRISPR-Cas9 based method to ablate MARCO in primary human macrophages. Along with our established model of perinatal liver inflammation, we will use these tools to address the following Specific Aims: Aim 1: Determine whether MARCO restricts immunoregulatory responses by directly inhibiting the IL-10 receptor; Aim 2: Determine whether MARCO inhibits antigen-specific regulatory responses in the liver; Aim 3: Test whether MARCO limits resolution of perinatal liver inflammation by inhibiting anti-inflammatory monocytes. Completion of the proposed Aims will define the role of MARCO in perinatal hepatic immune function and will yield important insights into how macrophage-mediated immune signals maintain the balance between immune regulation and immunity in the developing liver. Understanding these signals is critical to elucidating the pathogenesis of highly morbid liver diseases in pediatric patients and is the next important step for being able to design potential therapies.
