Autoimmune rheumatologic diseases
The paracaspase MALT1 is a key player in the activation of lymphoid, myeloid and mast cells, indicating MALT1's crucial role in innate and adaptive signaling. Therefore, MALT1 is regarded a promising target for the treatment of autoimmune diseases and defining its role in the pathogenesis of rheumatoid arthritis (RA) is a critical first step.
To unravel MALT1's role in RA, we initially assessed MALT1-activation in mice challenged with collagen-induced arthritis (CIA), the prototype model for RA. We then sought to address MALT1's role in the pathogenesis of RA by subjecting MALT1-deficient mice to the CIA model. To determine the importance of MALT1 in T-cells, CIA was additionally induced in CD4-specific MALT1-deficient mice. Finally, the effect of MALT1-deletion on bone homeostasis was assessed by measuring bone density by µCT-analysis of the tibiae and by a three-point bending test of the femurs.
We provide evidence that MALT1 is activated in RA and plays a crucial role in its pathogenesis since MALT1-deficent mice were completely protected against CIA. This protection was additionally observed in CD4-specific MALT1-deficient mice, indicating that the selective ablation of MALT1 in CD4-positive cells is sufficient for the observed resistance. Paradoxically to the protective effect of MALT1-deletion on inflammation, we show that MALT1-deficiency negatively influences bone density at steady state.
Altogether, our data provide evidence for a dual role of MALT1 in arthritis, showing a protective effect of its deletion on the inflammatory aspect and a negative effect on bone homeostasis.