As many as 1.4 million Americans suffer from chronic autoimmunity and inflammation associated with lupus, where autoantibody generation leads to accumulation of immune complexes that deposit in skin, vasculature, kidneys and other organs causing destructive, debilitating and sometimes life threatening, inflammation. Although lupus is of unknown etiology, it is clearly associated with the inefficient disposal of apoptotic cells, whih are considered the major source of lupus autoantigens. Complement component C1q triggers engulfment of apoptotic cells (efferocytosis), and deficiency in C1q is the strongest known susceptibility factor in lupus. While there has been a lot of attention given to the bridging function of C1q, which is a direct and immediate upregulation of phagocytosis, this is unlikely to explain its role in prevention of autoimmunity because a) it is not specific for apoptotic cell targets;and b) other C1q-related molecules, the collections, also upregulate immediate phagocytosis, but loss of these molecules is not associated with autoimmunity. Our preliminary data suggests an alternative hypothesis: C1q elicits a macrophage phenotype specifically tailored for engulfment of apoptotic cells. The data indicate that this pathway requires C1q- triggered macrophage expression of Mer and its ligand Gas6, an interaction that has been shown to regulate efferocytosis and limit inflammatory gene expression. The purpose of this grant is to define the new mechanism.
Specific aim one will investigate the requirement of Mer/Gas6 on C1q-dependent efferocytosis in vivo in mice, and in vitro using primary human phagocytes.
Specific aim two will investigate the signal transduction pathway leading to C1q- dependent upregulation of Mer. Adiponectin is a C1q-homologue that regulates efferocytosis and autoimmunity, and preliminary experiments demonstrate a role for adiponectin signaling and nuclear receptor activation in C1q-dependent Mer upregulation. Therefore, components of these signaling pathways will be analyzed using specific inhibitors and mouse models. The consequence of Mer deficiency on C1q/adiponectin-dependent regulation of proinflammatory cytokine production will be investigated in specific aim three using Mer wildtype and knockout mouse cells, as well as primary human phagocytes. The research will describe a novel pathway relevant to autoimmunity which should provide new molecular targets for therapeutics and diagnostics.
As many as 1.4 million Americans suffer from lupus, a chronic disease that affects skin, vasculature, kidneys and other organs causing destructive, debilitating and sometimes life threatening inflammation. A circulating protein called C1q regulates the immune response in lupus, and absence of C1q results in lupus in C1q-deficient people by an unknown mechanism. We have discovered a novel C1q-dependent molecular pathway relevant to lupus, and the purpose of this research is to further characterize the pathway in mouse and human cells with the eventual goal of identifying specific molecular targets for therapeutics and diagnostics in lupus and other autoimmune or inflammatory diseases.
|Galvan, Manuel D; Hulsebus, Holly; Heitker, Thomas et al. (2014) Complement protein C1q and adiponectin stimulate Mer tyrosine kinase-dependent engulfment of apoptotic cells through a shared pathway. J Innate Immun 6:780-92|