Luteolin reprograms macrophage polarization via the STING-TBK1 pathway to accelerate bone repair

Abstract

Macrophages play a pivotal role in bone regeneration, making their polarization a key target for immune regulation and therapeutic intervention. Modulating macrophage polarization represents a promising strategy for enhancing bone repair. Luteolin, a plant-derived flavonoid with well-documented anti-inflammatory properties, has been explored for its role in bone repair. However, its specific effects on macrophage polarization in bone repair remain unclear. This study investigates the role of luteolin in macrophage polarization and its underlying mechanisms. Our findings demonstrate that luteolin promotes M2 polarization while suppressing M1 polarization, as indicated by a reduction in the expression of pro-inflammatory markers, including IL-6 and iNOS, and an increase in the expression of anti-inflammatory factors, such as CD206, IL-10, and TGF-β. Mechanistically, luteolin inhibits STING oligomerization, thereby suppressing the STING-TBK1 pathway and mitigating downstream inflammatory responses. In vivo, in a mouse tibial bone defect model, luteolin effectively alleviates inflammation, facilitates angiogenesis, enhances collagen deposition, and improves bone density. Collectively, these findings highlight the potential of luteolin as a therapeutic agent for bone repair by modulating macrophage polarization and inhibiting STING-TBK1 signaling.

1. Introduction

Bone defects, characterized by compromised structural integrity and impaired regeneration, pose significant clinical challenges by disrupting biomechanical balance and sustaining inflammation [1,2]. Current treatments, such as autologous bone grafting and tissue-engineered scaffolds, have shown limited success due to issues such as immune rejection, poor osteoinductive potential, and inadequate vascularization [3‒8]. Thus, it is crucial to create advanced therapies that support bone regeneration and address the limitations of current treatments.

Macrophages are key players in the innate immune system, influencing both the initiation and resolution of inflammation [9]. Found in nearly all tissues, these versatile cells are involved in infection, tissue repair, and regeneration [10‒13]. Increasingly, macrophages are recognized for their role in bone healing, where they polarize into unique phenotypes (M1/M2) to regulate the inflammatory environment [14,15]. M1 macrophages are pivotal in the initiation of inflammatory responses through the secretion of key inflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6 [16]. These mediators trigger localized inflammation and promote the differentiation of monocytes into osteoclasts [17‒21], thereby accelerating bone resorption and contributing to a reduction in bone density. In contrast, M2 macrophages are involved in promoting tissue repair and regeneration through the secretion of diverse cytokines [22]. These cytokines support osteogenic differentiation, stimulate angiogenesis, and enhance extracellular matrix deposition, which collectively contribute to tissue healing and regeneration [23‒27]. Thus, modulating macrophage polarization represents a promising therapeutic approach for regulating bone homeostasis and enhancing bone regeneration, providing an effective strategy for the repair of bone tissue.