Small molecule inhibition of spleen tyrosine kinase mitigates gut-liver axis inflammation and histopathology in a novel model of IBD-associated liver disease.

Abstract

Abstract In light of recent studies identifying gain-of-function variants of spleen tyrosine kinase (Syk) as a cause of multi-organ inflammatory disease, Syk inhibition has become an attractive pharmacological target. Therapeutic potential of Syk inhibition may extend beyond that of gain-of-function mutations, since Syk activity initiates downstream responses to several pattern-recognition receptors, which are collectively thought to trigger pathology in several inflammatory diseases, including inflammatory bowel disease (IBD). We previously identified the IBD-linked gene Tnfaip3 (A20) as a suppressor of Syk-dependent inflammatory signals in dendritic cells (DCs) and report here that small molecule inhibition of Syk with FDA-approved drug Fostamatinib mitigates the small intestinal inflammation that develops spontaneously in mice with DC-specific loss of A20 (A20cko mice). In our investigation of IBD in these mice we surprisingly found that A20cko mice also had striking inflammation of the liver that shared many biochemical and histological features characteristic of IBD-associated liver disease, including extensive bridging fibrosis. Importantly, Syk inhibition normalized liver biochemistries and significantly reduced intrahepatic inflammation and fibrosis. Mechanistically, plasma proteomics and liver immunophenotyping pinpointed the key impact of Syk inhibition on restricting chemokine expression linked to recruitment of pro-inflammatory monocytes into in the liver. Collectively this work identifies the interplay of Syk and A20 signaling as drivers of inflammation along the gut-liver axis and suggests Syk is a valid target for pharmacological intervention for IBD and IBD-associated liver disease. Supported by R01AI145930-01A1