Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation.

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• Soluble CD95L (s-CD95L) binding to CD95 induces calcium responses via PLCγ1, promoting Th17 cell accumulation and lupus pathology.
• This pathway differs from membrane-bound CD95L (m-CD95L)-induced apoptosis, highlighting a distinct role in autoimmune disease.

Purpose of the Study:

• To investigate the role of the CD95-PLCγ1 interaction in lupus pathogenesis.
• To identify therapeutic agents that disrupt this interaction and ameliorate lupus symptoms.

Main Methods:

• Large-scale screening to identify inhibitors of the CD95-PLCγ1 interaction.
• Structure-activity relationship analysis of identified inhibitors.
• Synthesis of CD95-derived peptidomimetics.
• In vivo studies using lupus mouse models.

Main Results:

• Ritonavir, an HIV protease inhibitor, was identified as a potent disruptor of the CD95-PLCγ1 interaction.
• Ritonavir acts as a peptidomimetic, mimicking the calcium-inducing domain (CID) of CD95 for PLCγ1 docking.
• Synthesized CID peptidomimetics effectively abrogated CD95-mediated calcium responses and Th17 cell transmigration.
• Treatment with ritonavir or CID peptidomimetics alleviated clinical symptoms in lupus mice.

Conclusions:

• The CD95-PLCγ1 signaling pathway is a key driver of lupus pathology.
• Ritonavir and novel CID peptidomimetics represent a promising new therapeutic strategy for lupus.
• Targeting this pathway offers a novel avenue for drug development in autoimmune diseases.