Macrophages as a Source and Recipient of Wnt Signals

Abstract

Macrophages are often viewed through the lens of their core functions, but recent transcriptomic studies reveal them to be largely distinct across tissue types. While these differences appear to be shaped by their local environment, the key signals that drive these transcriptional differences remain unclear. Since Wnt signaling plays established roles in cell fate decisions, and tissue patterning during development and tissue repair after injury, we consider evidence that Wnt signals both target and are affected by macrophage functions. We propose that the Wnt gradients present in developing and adult tissues effectively shape macrophage fates and phenotypes. We also highlight evidence that macrophages, through an ability to dispatch Wnt signals, may couple tissue debridement and matrix remodeling with stem cell activation and tissue repair.

Keywords: Wnt signaling; beta catenin; immunity; macrophages; monocytes.

Figure 1

Tissue resident vs. recruited macrophages. Using lung as an example, tissue resident alveolar macrophages (TR-AM) self-renew to maintain surfactant homeostasis; monocytes are not recruited from the circulation (Left). After injury, TR-AMs are depleted and ultimately replaced by circulating monocytes (monocyte-derived alveolar macrophages, or Mo-AM) (Right). Upon injury, Mo-AMs are transcriptionally distinct from TR-AMs. Over time, Mo-AMs become transcriptionally indistinguishable from TR-AMs (7). The alveolar airway surface epithelium is lined by surfactant producing Alveolar Type 2 (AT2) and gas-exchange promoting Type 1 cells (AT1).

Figure 2

Wnt/β-cat signaling pathway. (A) In the absence of Wnt ligand, cytosolic β-cat is constitutively flagged for degradation by multi-protein complex comprising Adenomatosis Polyposis Coli (APC) protein, Axin, Casein Kinase 1 (CK-1), and Glycogen Synthase Kinase-3 beta (GSK-3β). (B) Wnt engagement of Frizzled (Fz) and low-density lipoprotein receptor-related protein 5 or 6 (Lrp5/6) inhibits β-cat turnover, favoring nuclear translocation and activation of target genes, including the negative feedback regulators zinc and ring finger proteins RNF43/ZNRF3. These E3 ligases antagonize Wnt signals by ubiquitylating Fz receptors, promoting their destruction. (C) R-spondins synergistically promote Wnt signals by binding leucine-rich repeat-containing G-protein coupled receptors (LGR4/5/6) and the E3 ligases RNF43/ZNRF3. This limits the ubiquitylation of Fz receptors, permitting enhanced activation of β-cat target genes. Non-canonical (i.e., β-cat-independent) Wnt signaling is not shown and described elsewhere (14).

Figure 3

Wnt signaling in monocyte-macrophage development and function post-infection or injury. Schematic representation of Wnt-directed macrophage phenotypes. (1) Growth factors M-CSF and GM-CSF upregulate β-cat/TCF levels, which may promote differentiation of myeloblasts into monocytes in developing if not adult contexts. (2–3) Wnts can be a downstream target of core inflammatory signals (e.g., Wnt5a by IL6/NFkB), where it may promote or limit phagocytic activity. (4) Wnt/β-cat signaling often promotes an anti-inflammatory macrophage phenotype (cytokines/genes shown). (5) Various cell types may be Wnt sources (e.g., fibroblasts, endothelia, as well as epithelia and macrophages).