# The Roles and Regulation of TLR7 in Systemic Lupus Erythematosus > **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $45,520 ## Abstract Project Summary: Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that causes significant morbidity and mortality. Despite this, there has been only one new FDA-approved therapy for SLE in the past 60 years, largely due to gaps in knowledge of disease mechanisms. In SLE, endosomal TLR7 and TLR9 are known to mediate the anti-self response. Surprisingly, our lab found that TLR9 deletion in the MRL.Faslpr model of SLE exacerbates disease, despite the requirement of TLR9 for formation of anti-chromatin antibodies. This exacerbation is dependent on TLR7, suggesting that TLR9 is protective while TLR7 drives pathology. A major goal of our lab is to understand these disparate roles of TLR7 and TLR9. We have found that the downstream adaptor of TLR7 and TLR9 (MyD88) is required to mediate nephrotoxic T cell activation in B cells and dermatitis development in dendritic cells. Thus, we hypothesize that TLR7 mediates different aspects of SLE pathology in different immune cell subsets. We will define these cell- specific roles by selectively deleting TLR7 in two MRL.Faslpr cohorts: one in B cells and the other in CD11c+ dendritic cells. We will comprehensively assess disease severity via kidney pathology, dermatitis, anti-self response, lymphadenopathy, and analysis of immune cell repertoire after onset of autoimmunity. Given that TLR7 exacerbates disease in the absence of TLR9, this will be repeated in TLR9-deficient mice to determine if this changes how TLR7 contributes to disease. Because of its pathogenic role, it also important to understand the regulation of TLR7. Our lab found that NOX2-deficient mice have remarkably worse disease, including increased anti-RNA autoantibody titers. The production of these autoantibodies is known to be TLR7-dependent. Recent work has shown that NOX2- dependent reactive oxygen species (ROS) can modify a TLR7-specific cysteine residue to inhibit anti-viral signaling. This cysteine, in the ectodomain of TLR7, has been shown to be required for RNA sensing and signaling. Taking all of this data into account, we hypothesize that loss of NOX2 exacerbates disease via dysregulation of TLR7. This will be studied using a twofold approach: First, we will cross NOX2-deficient to TLR7 deficient-mice to determine if exacerbated disease driven by the absence of NOX2 is dependent on TLR7. Second, we will use a mass spectrometry-based approach (OxMRM) in NOX2 deficient cells to determine how NOX2 signaling affects TLR7 oxidation state in SLE. This research will occur in the innovative, collaborative, and well-equipped environment of the M. Shlomchik laboratory at the University of Pittsburgh. The training plan related to this key research includes comprehensive instruction in bench work, data analysis, scientific communication and writing, and professional development. This will help me achieve my long-term goal of becoming an independent scientist that contributes to our knowledge of autoimmunity. ## Key facts - **NIH application ID:** 10065191 - **Project number:** 1F31AR077989-01 - **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH - **Principal Investigator:** Haylee Cosgrove - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $45,520 - **Award type:** 1 - **Project period:** 2020-08-01 → 2023-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10065191 ## Citation > US National Institutes of Health, RePORTER application 10065191, The Roles and Regulation of TLR7 in Systemic Lupus Erythematosus (1F31AR077989-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065191. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*