Targeting different phenotypes of macrophages: A potential strategy for natural products to treat inflammatory bone and joint diseases

Macrophages, a key class of immune cells, have a dual role in inflammatory responses, switching between anti-inflammatory M2 and pro-inflammatory M1 subtypes depending on the specific environment. Greater numbers of M1 macrophages correlate with increased production of inflammatory chemicals, decreased osteogenic potential, and eventually bone and joint disorders. Therefore, reversing M1 macrophages polarization is advantageous for lowering inflammatory factors. To better treat inflammatory bone disorders in the future, it may be helpful to gain insight into the specific mechanisms and natural products that modulate macrophage polarization. This review examines the impact of programmed cell death and different cells in the bone microenvironment on macrophage polarization, as well as the effects of natural products on the various phenotypes of macrophages, in order to suggest some possibilities for the treatment of inflammatory osteoarthritic disorders. Using 'macrophage polarization,' 'M1 macrophage' 'M2 macrophage' 'osteoporosis,' 'osteonecrosis of femoral head,' 'osteolysis,' 'gouty arthritis,' 'collagen-induced arthritis,' 'freund's adjuvant-induced arthritis,' 'adjuvant arthritis,' and 'rheumatoid arthritis' as search terms, the relevant literature was searched using the PubMed, the Cochrane Library and Web of Science databases. Targeting macrophages through different signaling pathways has become a key mechanism for the treatment of inflammatory bone and joint diseases, including HIF-1α, NF-κB, AKT/mTOR, JAK1/2-STAT1, NF-κB, JNK, ERK, p-38α/β, p38/MAPK, PI3K/AKT, AMPK, AMPK/Sirt1, STAT TLR4/NF-κB, TLR4/NLRP3, NAMPT pathway, as well as the programmed cell death autophagy, pyroptosis and ERS. As a result of a search of databases, we have summarized the available experimental and clinical evidence supporting herbal products as potential treatment agents for inflammatory osteoarthropathy. In this paper, we outline the various modulatory effects of natural substances targeting macrophages in various diseases, which may provide insight into drug options and directions for future clinical trials. In spite of this, more mechanistic studies on natural substances, as well as pharmacological, toxicological, and clinical studies are required.