Key points are not available for this paper at this time.
ABSTRACT Macrophage activation is an important feature of primary biliary cholangitis (PBC) pathogenesis and other cholestatic liver diseases. Galectin‐3 (Gal3), a pleiotropic lectin, is produced by monocytic cells and macrophages. However, its role in PBC has not been addressed. We hypothesized that Gal3 is a key to induce NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages and in turn to propagate proinflammatory IL‐17 signaling. In liver tissues from patients with PBC and dnTGF‐βRII mice, a model of autoimmune cholangitis, the expression of Gal3, NLRP3, and the adaptor protein adaptor apoptosis‐associated speck like protein was induced, with the downs tream activation of caspase‐1 and IL‐1β. Inwild‐typehepaticmacrophages, deoxycholic acid induced the association of Gal3 and NLRP3with direct activation of the inflammasome, resulting in an increase in IL‐1β. Downstreamretinoid‐related orphan receptor CmRNA, IL‐17A, and IL‐17Fwere induced. In Gal3 ‐/‐ macrophages, no inflammasome activation was detected. To confirm the key role of Gal3 in the pathogenesis of cholestatic liver injury, we generated dnTGF‐βRII/galectin‐3 ‐/ (dn/Gal3 ‐/ ) mice, which showed impaired inflammasome activation alongwith significantly improved inflammation and fibrosis. Taken together, our data point to a novel role of Gal3 as an initiator of inflammatory signaling in autoimmune cholangitis, mediating the activation of NLRP3 inflammasome and inducing IL‐17 proinflammatory cascades. These studies provide a rationale to target Gal3 in autoimmune cholangitis and potentially other cholestatic diseases.—Tian, J., Yang, G., Chen, H.‐Y., Hsu, D. K., Tomilov, A., Olson, K.A., Dehnad, A., Fish, S. R., Cortopassi, G.,Zhao, B., Liu, F.‐T., Gershwin, M.E., Török, N. J., Jiang, J. X. Galectin‐3 regulates inflammasome activation in cholestatic liver injury. FASEB J. 30, 4202–4213 (2016). www.fasebj.org
Tian et al. (Wed,) studied this question.