What happens when different lupus mechanisms hit the same pathway?

Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease, and one of the major challenges is understanding which signaling pathways represent common drivers across different disease mechanisms.

In this study, our postdoc Ales Drobek deepened into the question whether the SLC15A4-TASL signaling axis, which connects endolysosomal nucleic-acid sensing to IRF5 activation, is broadly required for lupus pathogenesis.

The answer was striking!

Using complementary genetic mouse models of lupus, each with different disease etiology, we found that disrupting SLC15A4-TASL signaling provided strong and durable protection from autoimmune disease.

Most notably, loss of this pathway:
·     prevented pathogenic age-associated B cell (ABC) accumulation
·     blocks autoantibody production
·     and protected from disease even when NF-κB and MAPK signaling remained intact

Our findings therefore identify SLC15A4-TASL as a central and nonredundant signaling node in nucleic-acid-driven autoimmunity, and support the potential of this pathway as a therapeutic target in SLE 💊

Happy reading! You can find the article here: https://www.pnas.org/doi/abs/10.1073/pnas.2618215123?af=R

This was a collaborative work with Vanja Sisirak lab. Big thanks to the Department of Immunobiology (DIB) – UNIL and especially to our animal facility in FBM UNIL – Faculté de biologie et de médecine de l’Université de Lausanne for untiring support!