A number of common kidney diseases are cause when antibodies in the form of immune complexes deposit in the kidney. The resulting kidney inflammation or glomerulonephritis is often destructive and progresses over time to end-stage kidney failure that requires dialysis or transplantation. Current therapies are non-specific, toxic and not always effective. There is a fundamental gap in the understanding of how antibody deposition in the kidney induces subsequent chronic inflammation. Toll-like receptors are cell surface receptors that usually function to induce immune responses to pathogens and are well conserved in all mammals. We hypothesize that endogenous ligands for Toll-like receptors are released following antibody deposition in the glomerulus and that such ligands serve as a "danger signal" that initiates injurious inflammatory responses in the glomerulus. In order to better understand the role of endogenous Toll-like receptor ligands during the pathogenesis of immune complex glomerulonephritis, we have developed a unique mouse model that mimics many of the characteristic features of immune complex glomerulonephritis in humans. In preliminary studies using this model, we discovered an important role of Toll-like receptor 7 (TLR7), a receptor activated by single stranded RNA, in the pathogenesis of immune complex glomerulonephritis.
In aim 1, we will define the source(s) of immunostimulatory RNA in the injured glomerulus and determine if Toll-like receptor 3, another RNA-sensing receptor, also plays a role in disease development.
In aim 2, we will identify the immune or kidney cells responsible for sensing endogenous RNA. As TLR7 engagement may activate several distinct signaling cascades, in aim 3 we will determine to what extent the different TLR7-induced cascades regulate disease phenotype and the rate of disease progression. Our long term goal is to use the detailed knowledge tht we will gain about pathogenic Toll-like receptor signaling pathways in mice to identify rational targets to treat immune complex disease in humans.
Immune complex-induced kidney diseases are the commonest cause of nephritis world-wide and a common cause of kidney failure in the USA. The proposed research will delineate the endogenous Toll-like receptor signaling pathways that are key mediators of destructive glomerular inflammation and proteinuria following antibody deposition in the kidney. Fundamental knowledge of these pathogenic pathways will provide rational targets for the development of future therapeutics for autoimmune kidney disease in human beings, as well as define transcriptional profiles indicative of prognosis.
|Gall, Jonathan M; Wang, Zhiyong; Bonegio, Ramon G et al. (2015) Conditional knockout of proximal tubule mitofusin 2 accelerates recovery and improves survival after renal ischemia. J Am Soc Nephrol 26:1092-102|
|Duffau, Pierre; Menn-Josephy, Hanni; Cuda, Carla M et al. (2015) Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model. Arthritis Rheumatol 67:3146-57|
|Watkins, Amanda A; Yasuda, Kei; Wilson, Gabriella E et al. (2015) IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis. J Immunol 194:1467-79|
|Yasuda, Kei; Watkins, Amanda A; Kochar, Guneet S et al. (2014) Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2. PLoS One 9:e103478|
|Aprahamian, Tamar R; Bonegio, Ramon G; Weitzner, Zachary et al. (2014) Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus. Immunology 142:363-73|
|Havasi, Andrea; Haegele, Joseph A; Gall, Jonathan M et al. (2013) Histone acetyl transferase (HAT) HBO1 and JADE1 in epithelial cell regeneration. Am J Pathol 182:152-62|
|Wang, Zhiyong; Gall, Jonathan M; Bonegio, Ramon et al. (2013) Nucleophosmin, a critical Bax cofactor in ischemia-induced cell death. Mol Cell Biol 33:1916-24|
|Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon et al. (2013) Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. J Immunol 191:2104-14|
|Yasuda, Kei; Nundel, Kerstin; Watkins, Amanda A et al. (2013) Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2. Int Immunol 25:295-306|