Systemic lupus erythematosus (SLE) is characterized by a variety of clinical and immunological manifestations. This proposal focuses on an animal model of lupus, pristane-induced lupus, which recapitulates many of the key features of human SLE including impaired phagocytosis of dead cells and their recognition by receptors of the innate immune system such as toll-like receptor 7 (TLR7). TLR7-stimulated proinflammatory cytokine production plays an important role in autoantibody production, nephritis, arthritis, and the hematological manifestations of lupus. However, preliminary studies suggest that diffuse alveolar hemorrhage (DAH) is TLR and cytokine independent and also independent of inflammasomes, suggesting that novel mechanisms are involved in lung inflammation. The long-term objective is to define the abnormal immunological pathways responsible for the clinical features of SLE. The central hypothesis is that lupus in pristane-treated mice and SLE patients is caused by impaired/altered phagocytosis of apoptotic cells, leading to inappropriate activation of several inflammatory pathways, which precipitate various aspects of the clinical syndrome.
Three Specific Aims are proposed:
Aim 1 addresses the mechanism of inflammation in DAH, examining the contribution of monocyte/macrophage subsets to the pathogenesis of lung inflammation.
Aim 2 addresses how pristane impairs the phagocytosis of dead cells by macrophages, leading to chronic inflammation instead of the normal anti-inflammatory response.
Aim 3 examines the relevance of pristane-induced lupus to the pathogenesis of inflammation and DAH in lupus patients. Taken together, these Aims will provide a more complete picture of why apoptotic cells are removed inefficiently in SLE patients and how this promotes chronic inflammation, autoimmunity, and tissue damage. Delineating the signaling pathways activated when dead cells are recognized by different macrophage subsets may suggest approaches to correct the phagocytic defect in SLE and/or treat its consequences. In particular, these studies may lead to new strategies for treating DAH, a complication of lupus that is fatal in over 50% of patients.

Public Health Relevance

Systemic lupus erythematosus is a serious autoimmune disorder, the etiology of which is incompletely understood. These studies will address the fundamental mechanisms responsible for disease pathogenesis in lupus patients. Understanding these immune mechanisms may lead to new treatments for serious complications of the disease such as diffuse alveolar hemorrhage, which has a mortality rate over 50%.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mancini, Marie
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University of Florida
Internal Medicine/Medicine
Schools of Medicine
United States
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Han, Shuhong; Zhuang, Haoyang; Shumyak, Stepan et al. (2018) Liver X Receptor Agonist Therapy Prevents Diffuse Alveolar Hemorrhage in Murine Lupus by Repolarizing Macrophages. Front Immunol 9:135
Han, Shuhong; Zhuang, Haoyang; Shumyak, Stepan et al. (2017) A Novel Subset of Anti-Inflammatory CD138+ Macrophages Is Deficient in Mice with Experimental Lupus. J Immunol 199:1261-1274
Zhuang, Haoyang; Han, Shuhong; Lee, Pui Y et al. (2017) Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus. Arthritis Rheumatol 69:1280-1293
Zhuang, Haoyang; Han, Shuhong; Li, Yi et al. (2016) A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM. Arthritis Rheumatol 68:2917-2928
Shumyak, Stepan; Yang, Li-Jun; Han, Shuhong et al. (2016) ""Lupoid hepatitis"" in SLE patients and mice with experimental lupus. Clin Immunol 172:65-71
Xu, Yuan; Zhuang, Haoyang; Han, Shuhong et al. (2015) Mechanisms of tumor necrosis factor ? antagonist-induced lupus in a murine model. Arthritis Rheumatol 67:225-37
Han, Shuhong; Zhuang, Haoyang; Xu, Yuan et al. (2015) Maintenance of autoantibody production in pristane-induced murine lupus. Arthritis Res Ther 17:384
Reeves, Westley H (2014) Editorial: systemic lupus erythematosus: death by fire and ICE? Arthritis Rheumatol 66:6-9
Pawar, Rahul D; Goilav, Beatrice; Xia, Yumin et al. (2014) Serum autoantibodies in pristane induced lupus are regulated by neutrophil gelatinase associated lipocalin. Clin Immunol 154:49-65
Zhuang, Haoyang; Han, Shuhong; Xu, Yuan et al. (2014) Toll-like receptor 7-stimulated tumor necrosis factor ? causes bone marrow damage in systemic lupus erythematosus. Arthritis Rheumatol 66:140-51

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