Signaling pathways in macrophages: molecular mechanisms and therapeutic targets

Abstract

Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.

Exploring the Therapeutic Potential of Ammodaucus leucotrichus Seed Extracts: A Multi-Faceted Analysis of Phytochemical Composition, Anti-Inflammatory Efficacy, Predictive Anti-Arthritic Properties, and Molecular Docking Insights

“…Furthermore, the prediction of matrix metalloproteinase (MMP) inhibition, particularly MMP9, suggests a potential avenue for joint protection in RA [ 61 , 62 ]. Transcription factor NF-κB, a key regulator of inflammation, was targeted by several compounds, providing insights into potential anti-inflammatory effects [ 63 , 64 ]. Notably, the hydrazide of 2-hydroxyacetohydrazide stands out, possibly due to its unique structure.…”

23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling

“…However, treatment with 23-HBA effectively inhibited STAT6 protein phosphorylation. The JAK2 protein has been reported to be activated and phosphorylated upon IL-4 binding to its receptors, which leads to the recruitment of STAT6 and its phosphorylation [ 21 , 22 ]. Interestingly, we found that the phosphorylation of JAK2 protein induced by IL-4 remained unaffected by 23-HBA, suggesting that 23-HBA inhibited the phosphorylation of STAT6 protein through a JAK2-independent pathway.…”

“…When IL-4 or IL-13 binds to the receptor, Janus kinase (JAK) is phosphorylated. This results in phosphorylation of tyrosine residues in the cytoplasmic region of the receptor, which provide multiple binding sites for the STAT6 molecule [ 21 , 22 ]. Once activated, STAT6 dissociates from the receptor to form a homodimer and enters the nucleus, where it binds to certain accessible DNA sequences, initiating the transcription of related genes and leading to the polarization of M2 macrophages [ 21 , 22 ].…”

“…This results in phosphorylation of tyrosine residues in the cytoplasmic region of the receptor, which provide multiple binding sites for the STAT6 molecule [ 21 , 22 ]. Once activated, STAT6 dissociates from the receptor to form a homodimer and enters the nucleus, where it binds to certain accessible DNA sequences, initiating the transcription of related genes and leading to the polarization of M2 macrophages [ 21 , 22 ]. Consequently, pharmacological inhibition of the STAT6 pathway emerges as a feasible strategy to regulate macrophage polarization, potentially impeding tumor progression and reducing chemoresistance in colorectal cancer.…”

Macrophage membrane-coated nanoparticles for the treatment of infectious diseases

“…Depending on phenotype and function, macrophages are usually classified into M0 (inactivated), M1 (pro-inflammatory, classically activated macrophages) and M2 (anti-inflammatory, alternatively activated macrophages) phenotypes [46][47][48]. Among them, M1 macrophages highly express co-stimulatory molecules, such as major histocompatibility complex class II (MHC-II), CD68, CD80 and CD86, and other inflammatory factors, such as interleukin (IL)-1β, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS) and interferon (IFN)-γ, which can activate other immune cells and promote inflammation [49,50]. In contrast, M2 macrophages phenotypically exhibit high expression of CD206 and CD163 and produce various cytokines, including arginase-1 (Arg-1), growth factors, angiogenic factors, and anti-inflammatory factors such as IL-10 and TGF-β, which negatively modulate immunity and promote tissue repair [51,52].…”