Regulation Of Immune Responses In Humans and in Experimental Animals

在巨噬细胞/树突状细胞中LRRK2信号功能的初步研究中，我们发现携带LRRK2转基因的小鼠细胞在暴露于先天配体时表现出增加的细胞因子反应，这些配体通过激活SYK来刺激细胞，SYK是一种细胞表面信号分子，参与dectin受体信号传导，在较小程度上参与TLR信号传导。这一点，再加上在Western blot研究中我们确定LRRK2与SYK以及下游SYK相关信号复合物组分相互作用的事实，BCL10/MALT-1/CARD9为LRRK2作为SYK信号通路组分的观点提供了重要支持。

In initial studies of LRRK2 signaling function in macrophages/dendritic cells we established that cells from mice bearing an LRRK2 transgene manifest increased cytokine responses when exposed to innate ligands that stimulate cells by activating SYK, a cell surface signaling molecule involved in dectin receptor signaling and to a lesser extent in TLR signaling. This, plus the fact that in Western blot studies we determined that LRRK2 interacts with SYK as well as with components of the downstream SYK-associated signaling complex, BCL10/MALT-1/CARD9 provided important support for the idea that LRRK2 acts as component of the SYK signaling pathway. In studies more specifically addressing how LRRK2 affects autophagy we found, somewhat to our surprise, that macrophages from LRRK2 transgenic mice upon stimulation of the dectin pathway exhibit decreased conversion of LC3 to LC3 II, the latter a molecule that appears at the distal end of the activated autophagy pathway. Complementary studies of macrophages from LRRK2-deficient mice showed that LRRK2 deficiency was associated with increased autophagy, thus confirming the result obtained with transgenic cells. In additional studies to address the issue of the molecular mechanism of LRRK2-mediated autophagy inhibition we showed that LRRK2 interacts with the autophagy initiator, beclin, and such interaction is associatd with breakdown of beclin dimers. Beclin breakdown may be mediated by caspase8 since LRRK2 also interacts with caspase8 and the latter is component of the BCL10 signaling complex mentioned above. Recent studies from other laboratories have shown that autophaphy leads to inhibition of activation and also to disturbances in IL-1beta signaling. The present studies therefore suggest that one of the mechanisms by which LRRK2 polymorphisms contribute to the inflammation of Crohn's disease is that these polymorphisms result in autophagy-related defects in the normal regulation of pro-inflammatory inflammasome/IL-1beta secretiion.