Target interactions for macrophage regulation: toward the development of therapeutics for cancer and inflammatory diseases

  • TODA Etsuko
    Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo 113-0031, Japan Laboratory for Morphological and Biomolecular Imaging, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo 113-0031, Japan Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, 2669 Yamasaki, Noda-city, Chiba 278-0022, Japan
  • TERASHIMA Yuya
    Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, 2669 Yamasaki, Noda-city, Chiba 278-0022, Japan

抄録

<p>Macrophages infiltrate lesions in diseases such as inflammation, tumors, and fibrotic tissues. Once recruited to the lesion sites, macrophages are activated and acquire diverse phenotypes depending on the stimuli in the microenvironment. Activated macrophages contribute to disease progression and are crucial targets in disease therapy because of their significant impact on immune responses through various effector functions, such as cytokine production, phagocytosis, and antigen presentation. Various approaches, including the regulation of macrophage recruitment, activation, and cancer suppression, have been demonstrated to have therapeutic effects. The challenge in modulating macrophages is that therapies aimed at regulating one aspect of macrophage properties may have unintended effects on another, potentially causing adverse effects. This review describes a therapeutic approach for regulating macrophages, focusing on FROUNT, a novel target molecule that induces macrophage migration and activation of regulatory molecules. FROUNT promotes signaling via chemokine receptors CCR2 and CCR5, modulating the intensity of chemokine signaling responses; thus, becoming a promising target for modulating macrophage function and safely controlling cancer and inflammation. By disrupting the interaction between FROUNT and chemokine receptors, we selectively regulated chemokine receptor signals mediated by FROUNT, suppressed the infiltration and activation of macrophages at lesion sites, and mitigated the pathogenesis of macrophage-related conditions such as nephritis and cancer. Targeting molecules that promote chemokine receptor–signaling could be a next-generation macrophage-targeted therapy with fewer side effects and higher efficacy than existing drugs for cancer and inflammation.</p>

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