LRRK2 as a negative regulator of NFAT: implications for the pathogenesis of inflammatory bowel disease

Inflammatory bowel disease encompasses two chronic, complex relapsing diseases believed to be caused by an excessive and poorly controlled immune response to the intestinal microbiota. The advent of genome-wide association scans has allowed for rapid identification of multiple susceptibility genes for Crohn's disease and ulcerative colitis. A locus containing LRRK2 and MUC19 is a confirmed Crohn's disease susceptibility locus. This genetic association precipitates an important functional study in which Liu et al. demonstrate that: LRRK2 acts as a negative regulator of NFAT in an NRON-dependent manner; LRRK2-deficient mice exhibit increased susceptibility to the development of dextran sodium sulfate colitis, which is enhanced by NFAT translocation to the nucleus; and patients exhibiting the risk LRRK2 allele have lower LRRK2 protein levels and exhibit less inhibition of NFAT. These data support the concept that defects within innate immunity trigger a robust adaptive immune response, which results in the production of proinflammatory cytokines and the development of chronic inflammation of the gastrointestinal mucosa.