Highlights d Myeloid-specific knockout of YAP relieves inflammatory bowel disease (IBD) d YAP regulates the balance between M1 and M2 polarization d YAP expression is differentially regulated by LPS/IFN-g and IL-4/13 treatment d YAP in macrophages affects the abundance of gut microbiota in IBD mice

Highlights d Multiple infections reduce DHCR7 expression but increase AKT3 expression in macrophages d DHCR7 deficiency and 7-DHC treatment activate the PI3K-AKT3 pathway d AKT3 binds IRF3 to enhance IRF3 Ser385 phosphorylation needed for full IRF3 activation d Targeting DHCR7 protects mice from various viral infections

Hepatocellular carcinoma (HCC) is frequently associated with pathogen infection-induced chronic inflammation. Large numbers of innate immune cells are present in HCCs and can influence disease outcome. Here, we demonstrated that the tumor suppressor serine/threonine-protein kinase 4 (STK4) differentially regulates TLR3/4/9-mediated inflammatory responses in macrophages and thereby is protective against chronic inflammation-associated HCC. STK4 dampened TLR4/9-induced proinflammatory cytokine secretion but enhanced TLR3/4-triggered IFN-β production via binding to and phosphorylating IL-1 receptor-associated kinase 1 (IRAK1), leading to IRAK1 degradation. Notably, macrophage-specific Stk4 deletion resulted in chronic inflammation, liver fibrosis, and HCC in mice treated with a combination of diethylnitrosamine (DEN) and CCl4, along with either LPS or E. coli infection. STK4 expression was markedly reduced in macrophages isolated from human HCC patients and was inversely associated with the levels of IRAK1, IL-6, and phospho-p65 or phospho-STAT3. Moreover, serum STK4 levels were specifically decreased in HCC patients with high levels of IL-6. In STK4-deficient mice, treatment with an IRAK1/4 inhibitor after DEN administration reduced serum IL-6 levels and liver tumor numbers to levels similar to those observed in the control mice. Together, our results suggest that STK4 has potential as a diagnostic biomarker and therapeutic target for inflammation-induced HCC.

R package LumiWCluster can be downloaded from http://www.unc.edu/∼pfkuan/LumiWCluster.