The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

Abstract

Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.

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ACKNOWLEDGMENTS

We thank the Central Animal Facility, Indian Institute of Science (IISc), for providing mice for experimentation. We thank Gordon Brown (Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom) for providing the mouse dectin-1 WT and mutant constructs. We thank Jun Nonomiya-Tsuji (North Carolina State University) for providing the TAK1 kinase-negative (KN) construct. We thank Akhihiko Yoshimura (School of Medicine, Keio University, Tokyo, Japan) for providing us the SOCS-1 OE construct. We thank Gary Owens (Cardiovascular Research Center, University of Virginia) for providing us the PIAS-1 OE construct. We thank Hiroaki Miki (RIMD, Osaka University, Japan) for NRX WT and Dsv1 constructs. We thank Roel Nusse (Department of Developmental Biology, Stanford University) for providing us WNT5A OE, β-catenin OE, and TCF4 DN constructs. Pannaga of the MCB imaging facility is acknowledged for her help. We acknowledge Pallavi Kakade for the timely help during the current course of investigation.

This study is supported by funds from the Department of Biotechnology (DBT), Department of Science and Technology (DST), Council for Scientific and Industrial Research (CSIR), and Indian Council of Medical Research (ICMR), Government of India, and the Indo-French Center for Promotion of Advanced Research (CEFIPRA). Infrastructure support from ICMR (Center for Advanced Study in Molecular Medicine), DST (FIST), and UGC (special assistance) (K.N.B.) and fellowships from CSIR (J.T. and, V.S.) and IISc (S.H., K.M., and P.P.) are acknowledged.