There are few effective clinical strategies to prevent or treat liver fibrosis or ensuing cirrhosis. The transmembrane receptor Dectin-1 is a member of the C-type lectin family of pattern recognition receptors which are cousins of the Toll-like receptor (TLR) family. Although Dectin-1 is required for the innate immune response to fungal pathogens, it does not have an established role in modulating sterile inflammation in any context. Based on robust preliminary data, our hypothesis is that Dectin-1 signaling protects against liver fibrosis by two distinct mechanisms: (i) delimiting TLR4 activation in response to hepatic injury, and (ii) directly promoting hepatic regeneration. This proposal is highly novel, given that this is the first investigation of a role for Dectin-1 in non-pathogen-driven sterile inflammation.
In Aim 1 we will investigate the expression of novel Dectin-1 ligands and upregulation of activated Dectin-1 signaling intermediates in murine and human liver fibrosis. These data will indicate the relevance of endogenous Dectin-1 signaling to the modulation of liver fibrosis in humans and mice. We will then test our primary hypothesis by directly assessing whether deletion of Dectin-1 exacerbates liver fibrosis and whether ligation of Dectin-1 protects against liver fibrosis.
In Aim 2 we will determine whether Dectin-1 signaling protects against live fibrosis by mitigating TLR4 activation. We will investigate novel cross-regulation between Dectin-1 and TLR4 in liver macrophages and hepatic stellate cells and determine the complex mechanisms governing Dectin-1 suppression of TLR4 signaling in vivo in liver disease. Collectively, these experiments will provide mechanistic insight into how Dectin-1 suppresses TLR4-mediated hepatic fibro-inflammatory disease.
In Aim 3 we will explore a mechanistic avenue that is independent of the Dectin-1-TLR4 interface. Specifically, we postulate that Dectin-1 mitigates liver fibrosis by promoting hepatic regeneration. We will investigate the role o Dectin-1 in hepatocyte proliferation in the fibrotic liver and after partial hepatectomy and determine the mediators of this process. When completed, we expect that our work will suggest that Dectin-1 signaling protects against hepatic fibro-inflammatory disease and may be an attractive target for disease prophylaxis or experimental therapies. Moreover, the importance of our work extends beyond chronic liver fibrosis; it promises to decipher critical signaling mechanisms that govern hepatic regeneration and regulation of sterile inflammation which are necessary to maintain physiologic homeostasis in health and disease.
Regulation of hepatic fibrosis is incompletely understood. We postulate that Dectin-1 signaling protects against hepatic fibro-inflammatory disease. Our work will provide a novel target for experimental therapeutics in hepatic fibrosis and have will pleiotropic implications beyond liver fibrosis to the regulatory implications of Dectin-1 in allied sterile inflammatory conditions.
