CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis

• Published in: bioRxiv
• Main Authors: Li, Xiaobo, Villanueva, Veronica, Jimenez, Viviana, Nguyen, Billy, Chauhan, Nishant Ranjan, Khan, Samia Q, Dorschner, Jessica M, Jensen, Mark A, Alzahrani, Khulood, Wei, Huiting, Cimbaluk, David J, Wei, David C, Jolly, Meenakshi, Lopez-Rodriguez, Darlah, Pineda, Santiago Balza, Barbosa, Antonio, Vazquez-Padron, Roberto I, Faridi, Hafeez M, Reiser, Jochen, Niewold, Timothy B, Gupta, Vineet
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory 26.07.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.07.26.605143

Lupus Nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that affects kidney function. Here, we investigated the role of CD11b, a protein encoded by the gene, in the development of LN and its functional activation as a therapeutic strategy. Genetic coding variants of significantly increase the risk for SLE and LN by producing a less active CD11b and leading to elevated levels of type I interferon (IFN I). However, a molecular mechanism for how these variants increase LN risk has been unclear. Here, we determined that these variants also significantly associate with elevations in soluble urokinase plasminogen activator receptor (suPAR), a known biomarker linked to kidney disease, suggesting a novel molecular connection. Pharmacologic activation of CD11b with a novel, clinical-stage agonist ONT01 significantly suppressed suPAR production in myeloid cells and reduced systemic inflammation and kidney damage in multiple experimental models of LN. Importantly, delaying treatment with ONT01 until after disease onset also significantly reduced serum suPAR and inflammatory cytokines, and decreased immune complex deposition in the glomerulus, glomerulonephritis and albuminuria, suggesting that CD11b activation is therapeutic for LN. Genetic activation of CD11b via a gain-of-function CD11b mutation also showed complete protection from LN, whereas genetic deletion of CD11b worsened the disease in mice, providing further evidence of the role of CD11b activation in regulating LN. Finally, transfer of human LN PBMCs generated human LN like disease in mice that was significantly reduced by ONT01. Together, these data provide strong evidence that ONT01 mediated CD11b activation can therapeutically modulate TLR7-driven inflammation and protect against LN. These findings support clinical development of CD11b agonists as novel therapeutics for treating lupus nephritis in human patients.