We indentified ABIN1/TNIP1 as component of the TLR signaling complex, which is essential to counteract pro-inflammatory TLR signaling. Human TNIP1 is genetically linked to the inflammatory diseases “systemic lupus erythematosus (SLE)“ and “psoriasis“ (hypomorphic polymorphisms). SLE is an “autoimmune“ disease of unclear etiology characterized by auto-antibodies and inflammatory infiltration of many organ systems. Immune complex-deposits in the kidneys are believed to drive glomerulonephritis leading to kidney failure. Psoriasis is an chronic, inflammatory skin disease, characterized by proliferating epidermal cells (keratinocytes), leading to red, scaling patches.
OUR MAJOR OBSERVATIONS
TNIP1-/- mice develop constitutively the major symptoms of human SLE and, inducibly, psoriasis-like disease. Consistent with current models, SLE is driven by nucleic acid-recognizing TLRs (TLR7/9, MyD88), while psoriasis is driven by the IL-17R.
Surprisingly, genetic deletion of T- and B-cells (and thus IgG) did not provide protection from kidney disease. In contrast, we found that a monocyte subtype (Patrolling monocytes, Pmo), accumulates in kidney glomeruli and, intruigingly, that genetic deletion of PMo protected from GN. As such, innate immune cells, not B-cell-derived auto-antibodies promote GN, suggesting a shift in paradigm with important ramnifications for human disease and therapeutic approaches.
We explore the mechanism of patrolling monocyte (PMo) deregulation. We investigate why PMo are up-regulated (cell differentiation vs. survival) and study the contribution of C/EBPb to PMo deregulation and disease. We also investigate established and novel therapeutic strategies to prevent PMo- mediated disease.