Defining MARCO as an innate checkpoint in SLE

About This Grant

Project Summary Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease triggered by aberrant activation of the immune system. 1.5 million Americans are affected in the United States alone, and 5 million individuals worldwide. Toll-like receptors (TLRs) play a critical role in the pathogenesis of SLE. While nucleic acid sensing TLRs are required to produce autoantibodies specific for DNA and RNA binding autoantigens, myeloid cells such as macrophages also play an important role in initiating but also resolving the immune responses which underpin SLE. Surveillance of the tissue microenvironment by tissue resident macrophages (TRMs) promotes homeostasis, immune cell recruitment, protection from tissue damage and the resolution of immune responses. Dysregulation of TRM function has been previously implicated in the progression of SLE. However, the precise mechanisms that regulate the function of TRMs in SLE remain unresolved. Thus, there is an urgent need to understand how TRMs regulate the onset and resolution of inflammation in SLE. Tissue resident macrophages can be characterized by specific markers including the scavenger receptor Macrophage Associated Receptor with Collagenous Structure (MARCO). When expressed on the cell surface, MARCO can be decorated with N-linked glycan chains which facilitate binding to pathogens. Interestingly, interferons (IFNs) suppress expression of the scavenger receptor MARCO on macrophages and hence, limit clearance of apoptotic debris and immune complexes. However, how this pathway is regulated and its impact on the outcome of SLE is unknown. Through this proposal, we will develop and validate novel concepts and experimental models to understand the IFN-MARCO signaling axis and how the suppression of MARCO promotes manifestations of SLE. Our studies will define the immunological crosstalk established between IFNs and TRMs and unravel the signaling events that orchestrate these events. Our research aims to definitively define how the IFN-MARCO signaling axis contributes to the pathogenesis of SLE.