Friday, November 22, 2024
11/22/2024
DESCRIPTION (provided by applicant): 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 collectins, 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 AMP-activated protein kinase (AMPK) activation in C1q-dependent Mer upregulation. Therefore, components of these signaling pathways will be analyzed using biochemical techniques. 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.
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