Rheumatoid arthritis (RA) is an autoimmune disease characterized by hyperplasia of the synovial lining, inflammation, and destruction of cartilage and bone. In RA, the balance between anti- and pro-apoptotic members of the Bcl-2 family may be shifted towards survival. We demonstrated that the anti-apoptotic proteins, Bcl-2 and Mcl-1 are increased while the pro-apoptotic protein Bim is decreased in RA synovial tissue as compared to controls. The study of deficiencies in anti-apoptotic members of the Bcl-2 family is complicated by embryonic lethality or early post-natal death. In contrast, mice deficient in pro-apoptotic Bcl-2 members such as Bak, Bax, or Bim survive and reach adulthood. Since Bim is a critical activator of apoptosis through sequestering Bcl-2/Mcl-1 and/or by activating Bak and Bax and since Bim is decreased in RA synovial tissue, Bim is a potential target for treatment of RA. We demonstrated that mice lacking the apoptotic initiator Bim but not the downstream effectors Bak or Bax develop a more severe form of inflammatory arthritis. This exacerbated disease in Bim-/- mice is associated with decreased apoptosis, increased expression of pro-inflammatory molecules, and more macrophages in pannus. Further, Bim-/- macrophages display elevated levels of IL-6, IL-1?, and TNFa and enhanced expression of CD40 and CD69 in response to stimulation with LPS. Based on these data, we hypothesize that the ratio of Bim to Bcl-2 and/or Mcl- 1 serves as molecular rheostat that determines the extent of hyperplasia and activation of macrophages in the joint. We will use a pharmacological approach, a whole animal approach, and a cell-specific approach to identify how deficiency in Bim exacerbates inflammatory arthritis. These studies will potentially lead to novel therapeutic approaches to RA. The regulation of cell death and growth is vital for maintaining a balance in the human body. However, during the initiation and/or progression of the autoimmune disease, rheumatoid arthritis (RA), the balance is disrupted. In RA there is an increase in cellular growth and a concomitant decrease in cell death leading to an abnormal increase in the tissue that attaches to the cartilage/bone junction, the synovial lining. Analysis of tissue from joints of patients with RA revealed that the number of macrophages correlated with a worse prognosis. Monocytes (macrophage precursors) and macrophages are immune cells that produce the noxious factors in patients with RA and are responsible for removing dying cells or debris in tissues. We demonstrated that the death signaling cascade mediated by the pro-death protein Bim is dysfunctional in macrophages from patients with RA. Additionally, we have shown that mice lacking Bim in all cell types develop a worse form of arthritis and that the macrophages from these mice are highly activated, meaning they produce significant amounts of deleterious factors that exacerbate the inflammation. Therefore, our goal is to develop a therapeutic to activate the Bim death pathway and inhibit or induce remission in RA. Further our goal is to characterize mice lacking Bim or it signaling partners only in monocytes and macrophages. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI067590-01A2
Application #
7314996
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2007-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$220,500
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086
Cuda, Carla M; Misharin, Alexander V; Gierut, Angelica K et al. (2014) Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. J Immunol 192:5548-60
Cuda, Carla M; Agrawal, Hemant; Misharin, Alexander V et al. (2012) Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice. Arthritis Rheum 64:808-20
Mavers, Melissa; Cuda, Carla M; Misharin, Alexander V et al. (2012) Cyclin-dependent kinase inhibitor p21, via its C-terminal domain, is essential for resolution of murine inflammatory arthritis. Arthritis Rheum 64:141-52
Budinger, G R Scott; Mutlu, Gökhan M; Urich, Daniela et al. (2011) Epithelial cell death is an important contributor to oxidant-mediated acute lung injury. Am J Respir Crit Care Med 183:1043-54
Misharin, Alexander V; Scott Budinger, G R; Perlman, Harris (2011) The lung macrophage: a Jack of all trades. Am J Respir Crit Care Med 184:497-8
Urich, Daniela; Eisenberg, Jessica L; Hamill, Kevin J et al. (2011) Lung-specific loss of the laminin ?3 subunit confers resistance to mechanical injury. J Cell Sci 124:2927-37
Scatizzi, John C; Hutcheson, Jack; Pope, Richard M et al. (2010) Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis. Arthritis Rheum 62:441-51
Perlman, Harris; Pope, Richard M (2010) The synovial lining micromass system: toward rheumatoid arthritis in a dish? Arthritis Rheum 62:643-6
Gierut, Angelica; Perlman, Harris; Pope, Richard M (2010) Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am 36:271-96

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