Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation

Xiaoyu Hu^*, Janice Chen, Lu Wang^* and Lionel B. Ivashkiv^*^,^,1

^* Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA; and
Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA

¹ Correspondence: Hospital for Special Surgery, 535 East 70th Street, Research Building, Room 400, New York, NY 10021, USA. E-mail: ivashkivl{at}hss.edu

ABSTRACT

Macrophage phenotype and activation are regulated by cytokinesthat use the Jak-STAT signaling pathway, microbial recognitionreceptors that include TLRs, and immunoreceptors that signalvia ITAM motifs. The amplitude and qualitative nature of macrophageactivation are determined by crosstalk among these signalingpathways. Basal ITAM signaling restrains macrophage responsesto TLRs and other activating ligands, whereas strong ITAM signalssynergize with the same ligands to activate cells strongly.Similarly, basal ITAM signaling augments IFN signaling and functionof receptor activator of NF- ${kappa}$ B, but extensive ITAM activationinhibits Jak-STAT signaling. Thus, intensity and duration ofITAM signaling determine whether ITAM-coupled receptors augmentor attenuate TLR and Jak-STAT responses. IFN- ${gamma}$ synergizes withTLRs in part by suppressing TLR-induced feedback inhibition,mediated by IL-10 and Stat3, by a mechanism that depends onglycogen synthase kinase (GSK)3 regulation of AP-1 and CREB.IFN- ${gamma}$ suppresses TLR2 and TLR4 induction/activation of AP-1 byoverlapping mechanisms that include regulation of MAPKs, GSK3-dependentsuppression of DNA binding, and decreased Fos and Jun proteinexpression and stability. IFN- ${gamma}$ suppression of TLR-induced activationof AP-1 and downstream target genes challenges current conceptsabout the inflammatory role of AP-1 proteins in macrophage activationand is consistent with a role for AP-1 in the generation ofnoninflammatory osteoclasts. Jak-STAT, TLR, and ITAM pathwaysare basally active in macrophages and strongly induced duringinnate responses. Thus, signal transduction crosstalk is regulatedin a dynamic manner, which differs under homeostatic and pathologicconditions, and dysregulation of signal transduction crosstalkmay contribute to pathogenesis of chronic inflammatory diseases.

Key Words: cytokine • AP-1/CREB • RANK