Lupus nephritis (LN) is a debilitating inflammatory disease that is caused by Systemic Lupus Erythematosus (SLE, lupus). Poorly defined genetic and environmental factors predispose lupus patients for renal disease. Approx. 40% of lupus patients show renal impairment and a large percentage develop end stage renal disease (ESRD). Women, especially young women of childbearing age, are more susceptible to LN, suggesting role of early glomerular injury in LN. LN is managed by glucocorticoids and immunosuppressive agents, with many side effects and considerable long-term toxicity. Therefore improved, targeted treatments are urgently needed. Three single nucleotide polymorphisms (SNPs) in the coding region of ITGAM gene (coding for CD11b), show strong correlation with the incidence of LN (and SLE). However, how these nonsynonymous mutations confer SLE risk is not clear, although that they appear to reduce the biological functions of CD11b. Given that glomerular leukocyte influx in increased in LN, this is paradoxical, as CD11b is widely considered to play a major role in leukocyte infiltration. Here, we present data that CD11b activation plays a major role in suppressing Toll like receptor (TLR) signaling pathways. IFN I is increased in sera of LN patients, and suPAR is a circulating risk factor for glomerular diseases. Since both biomarkers are generated downstream of the TLR-pathways, we hypothesize that there is a direct link between coding ITGAM SNPs and the levels of these two biomarkers in LN and that this is due to the failure of the mutant CD11b protein product to suppress TLR signaling. We also hypothesize that forced activation of CD11b can reduce TLR signaling, is sufficient to decrease IFN I and suPAR level, thereby ameliorating disease activity. We also hypothesize that activation of CD11b using a pharmacologic small molecule LA1 recently discovered in our laboratory, or via genetic mutations, can rescue the functional deficit of the mutant CD11b protein and suppress TLR-dependent inflammatory signaling. Therefore, we propose that CD11b activation can be a new therapeutic strategy for the development of novel therapeutics for LN. In this proposal, we present three specific aims to test our hypotheses. These studies will help mechanistically connect a common genetic factor associated with SLE and LN with important clinical biomarkers, and will provide us with an improved understanding of the disease pathways. More importantly, the studies will also help determine if CD11b activation could be a novel mechanism to treat LN, as well as define the efficacy of a novel small molecule, LA1, which could potentially lead to the development of LA1 (or other similar agents) as novel therapeutics to treat LN patients. This may also lead to the development of a first potential therapy targeting a specific susceptibility gene (ITGAM) in an autoimmune disease. Thus, this comprehensive translational study has the potential for making a large beneficial impact on the LN patients in the future.
Increased inflammation is a driver behind a number of glomerular diseases, including lupus nephritis, and novel therapeutics are urgently needed. The studies proposed here will lead to the development of new types of targeted therapeutics and strategies for reducing glomerular injury and for treating lupus nephritis in patients.
|Khan, Samia Q; Khan, Imran; Gupta, Vineet (2018) CD11b Activity Modulates Pathogenesis of Lupus Nephritis. Front Med (Lausanne) 5:52|
|Dickinson, Catherine M; LeBlanc, Brian W; Edhi, Muhammad M et al. (2018) Leukadherin-1 ameliorates endothelial barrier damage mediated by neutrophils from critically ill patients. J Intensive Care 6:19|
|Faridi, Mohd Hafeez; Khan, Samia Q; Zhao, Wenpu et al. (2017) CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest 127:1271-1283|
|Lee, Ha Won; Khan, Samia Q; Khaliqdina, Shehryar et al. (2017) Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1. J Biol Chem 292:732-747|
|Johnson, Courtney M; O'Brien, Xian M; Byrd, Angel S et al. (2017) Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal ?-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response. J Immunol 198:318-334|
|Reiser, Jochen; Lee, Ha Won; Gupta, Vineet et al. (2017) A High-Content Screening Technology for Quantitatively Studying Podocyte Dynamics. Adv Chronic Kidney Dis 24:183-188|
|Hahm, Eunsil; Wei, Changli; Fernandez, Isabel et al. (2017) Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23:100-106|
|Lee, Ha Won; Khan, Samia Q; Faridi, Mohd Hafeez et al. (2015) A Podocyte-Based Automated Screening Assay Identifies Protective Small Molecules. J Am Soc Nephrol 26:2741-52|
|Jagarapu, Jawahar; Kelchtermans, Jelte; Rong, Min et al. (2015) Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats. Am J Respir Cell Mol Biol 53:793-801|
|Rodriguez-Menocal, Luis; Faridi, Mohd Hafeez; Martinez, Laisel et al. (2014) Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling. Am J Physiol Heart Circ Physiol 306:H641-53|
Showing the most recent 10 out of 17 publications