Macrophages and Wnts in Tissue Injury and Repair

Abstract

Macrophages are important players in the immune system that sense various tissue challenges and trigger inflammation. Tissue injuries are followed by inflammation, which is tightly coordinated with tissue repair processes. Dysregulation of these processes leads to chronic inflammation or tissue fibrosis. Wnt ligands are present both in homeostatic and pathological conditions. However, their roles and mechanisms regulating inflammation and tissue repair are being investigated. Here we aim to provide an overview of overarching themes regarding Wnt and macrophages by reviewing the previous literature. We aim to gain future insights into how tissue inflammation, repair, regeneration, and fibrosis events are regulated by macrophages.

Keywords: Wnt; inflammation; macrophage.

Figure 1

The canonical and non-canonical Wnt signaling pathways. In the canonical Wnt pathway, the Wnt signaling is activated upon binding Wnt ligands such as Wnt3a to Frizzled (FZD) and co-receptor LRP5/6. Then, the Disheveled (Dvl) recruits axis inhibition protein (Axin), the casein kinase 1 (CK1), and glycogen synthase kinase 3 β (GSK3β) to the plasma membrane, inactivating the β-catenin destruction complex and weakening phosphorylation and degradation of β-catenin. This results in the accumulation of the stabilized β-catenin in the cytoplasm and the translocation of it into the nucleus. β-catenin in the nucleus forms an active transcriptional complex with T-cell factor (TCF) and lymphoid enhancer factor (LEF), leading to canonical Wnt target gene expression. Upon the non-canonical Wnt ligands such as Wnt5a binding to the RYK/ROR2-FZD complex, Dvl is recruited, and Wnt/PCP or Wnt/Ca²⁺ signaling pathway is activated. In the Wnt/PCP pathway, the scaffold protein Dvl stimulates the activation of the small GTPase Rho and RAC to induce Rho-associated kinase (ROCK) and c-Jun N-terminal kinase (JNK), respectively. ROCK and JNK trigger gene expression associated with cell polarization and cytoskeletal rearrangement. In the Wnt/Ca²⁺ pathway, Dvl activates phospholipase C (PLC), stimulating 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). The activated IP3 promotes the release of Ca²⁺ within the cytoplasm, and protein kinase C (PKC), CAMKII, and calcineurin are subsequently induced. The nuclear factor of activated T-cells (NFAT), a transcriptional factor, is then activated through dephosphorylation to induce calcium-dependent cytoskeletal and transcriptional responses.

Figure 2

Macrophage development and functions in different organs. Tissue-resident macrophages are originated from the yolk sac/fetal liver and hematopoietic progenitors/circulating monocytes. Monocytes are further differentiated into M1-like and M2-like macrophages based on their expression markers upon a variety of stimuli. M2-like macrophages are known to be important for wound repair and also share similar features with TAMs. M1-like macrophages constitute the first line of defense against intracellular pathogens. Macrophages are sources of Wnt ligands and mediate Wnt ligand-mediated signaling for various immune responses for tissue inflammation and repair. This was created with Biorender.com.