The Context-Dependent Role of Wnt Signaling in Macrophage Cytokine Production.

Abstract

Macrophages exhibit considerable functional plasticity in response to environmental cues, contributing to inflammatory initiation, amplification, resolution, tissue remodeling, and tumor progression. Wnt signaling has emerged as an important regulator of these processes, yet its effects vary with the signaling branch, cellular context, and duration of stimulation. This review examines the roles of canonical and typical non-canonical Wnt signaling in macrophage inflammatory regulation with a focused view on signaling pathways at the intersection of Wnt signaling with nuclear factor-κB (NF-κB) in macrophages. Rather than treating these pathways as independent regulators or categorizing their effects as simply pro- or anti-inflammatory, we examine their shared signaling components, subcellular organization, and transcriptional interactions. Particular attention is given to compartment-specific β-catenin-NF-κB crosstalk and the potential role of TCF4 in coordinating gene-selective inflammatory responses, alongside Wnt5a-mediated regulatory circuits that link non-canonical signaling to innate immune competence and inflammatory activity. We further consider the functional significance of these mechanisms across inflammatory responses, tissue remodeling, and tumor-associated macrophage reprogramming. By integrating molecular mechanisms with macrophage functional plasticity, this review highlights how Wnt signaling may shape distinct inflammatory outcomes according to cellular and disease context. This framework identifies key mechanistic gaps and provides a basis for investigating Wnt-associated regulatory nodes as potential therapeutic targets while accounting for the need to preserve physiological macrophage functions.