Immune and inflammatory mechanisms critical to the development of SLE, with a focus on RIPK3-dependent pathways

Dr. Joyce Rauch, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec

Principal: Dr. Joyce Rauch

Team members: Céleste Pilon, Elena Lonina, Dr. Jerrold S. Levine, Dr. Maziar Divangahi, Dr. Ciriaco Piccirillo, Dr. Jose A. Correa, Dr. Suman Setty, Dr. Marvin Fritzler and Dr. Christian Pineau

Our findings will provide proof of concept that targeting RIPK3 (Receptor-Interacting Protein Kinase 3)-dependent pathways in murine SLE results in prevention or improvement of this chronic and debilitating disease. These data could lead to Phase I trials of new therapeutic agents targeting RIPK3-dependent mechanisms in patients with SLE, which would impact both knowledge and patient care, and lead to improved treatments in SLE.

RIPK3 (Receptor-Interacting Protein Kinase 3) is a master regulator of cell death and inflammation. We have shown that deletion of RIPK3 prevents the development of SLE in an induced murine model. We hypothesize that RIPK3-dependent pathways are critical to the development of SLE, and that therapeutically targeting RIPK3 will prevent or ameliorate SLE.

We have published the following paper (Salem et al., lmmunol. Cell. Biol., 2019) related to this project demonstrating the following novel findings:

• β2-glycoprotein I (β2GPI), the self-antigen that induces our model of SLE, binds to cells dying by a RIPK3-dependent process (“necroptosis”).
• Necroptosis promotes activation of T cells reactive with β2GPI that help in the production of SLE autoantibodies.
• Targeting RIPK3 (by depletion in mice) results in reduced autoantibody production and kidney disease in a murine model of SLE.

https://onlinelibrary.wiley.com/doi/abs/10.1111/imcb.12279

These and future findings will provide proof of concept that inhibition of RIPK3-dependent pathways can diminish and/or prevent the development of murine SLE. This research will spur the development of novel diagnostic and therapeutic approaches in SLE, impacting both knowledge and patient care.

Current funding: CIHR Project Grant (PJT-159652)