Uncovering novel mechanistic pathways involved in immune cell-mediated pathogenesis of autoimmune rheumatic diseases has been a consistent theme throughout my research career. Systemic lupus erythematosus (SLE) is a multi-organ and destructive autoimmune disease characterized by pathogenic autoantibodies. While it has been accepted that dendritic cells play an important role in the initiation of the disease, only recently have studies now implicated DCs as a major factor in the persistence of SLE. DCs from patients with SLE exhibit elevated expression of activation markers including co-stimulatory molecules and pro- inflammatory cytokines;however, the factors that are responsible for the aberrant activation is unknown. Caspase 8, an aspartic enzyme known to function in death receptor signaling, can initiate apoptosis and/or suppress necroptosis (through inhibition of RIPK1/3 signaling) in a multitude of cells. Preliminary studies show that mice lacking caspase 8 in DCs (CreCD11cCasp8flox/flox), exhibit a break in tolerance at as early as 2-3 months of age. CreCD11cCasp8flox/flox mice display splenomegaly, lymphadenopathy, dsDNA-reactive autoantibodies, glomerulonephritis, immune complex deposition in the kidney, exacerbated proteinuria levels, heightened amounts of serum pro-inflammatory cytokines (IL-12, IL-1?, and IFN?/?)and early mortality. Loss of caspase 8 in DCs does not affect their survival, but they are highly activated, leading to elevated levels of activated lymphocytes in a paracrine manner. The increased activation potential of CreCD11cCasp8flox/flox DCs may be controlled by toll-like receptos 7 and 9 (TLR7/9) since caspase 8-deficient DCs display a hyper- responsiveness to TLR7/9 ligation with increased DNA binding activity of interferon regulatory factor (IRF). Additionally, blocking RIPK1 signaling dampens the TLR7/9-induced secretion of pro-inflammatory cytokines in caspase 8-deficient DCs. Collectively, these data suggest that intact caspase 8 signaling in DCs is crucial for preventing and/or limiting the hyper stimulation of DCs and induction of SLE-like disease. My progress and career advancement will be monitored throughout the five-year program by an Advisory Committee, which will include my mentor and four other members, and this group has already been instrumental in helping me develop my research proposal. My long-term career goal has been to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic diseases, with an emphasis on systemic lupus erythematosus (SLE). It is my belief that this proposal is an ideal training vehicle for a K01 Mentored Research Scientist Development Award, as I will become proficient in DC biology, as well as signal transduction, thereby developing my own niche in rheumatic disease as I begin to establish an independent academic career.
Aberrant dendritic cell phenotypes are observed in patients with systemic lupus erythematosus (SLE). This proposal suggests that intact caspase 8 signaling in dendritic cells (DCs) is crucial for preventing and/or limiting the hyper stimulation f DCs and induction of SLE-like disease. Since patients with SLE often fail to achieve remission using current immunosuppressive therapy, relapses are common, and side effects from treatment are substantial, the ultimate objective is to utilize these research discoveries to help n the development of safer and more effective therapies for rheumatic diseases.
|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|
|Khare, Sonal; Ratsimandresy, Rojo A; de Almeida, Lúcia et al. (2014) The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol 15:343-53|