The role of immune cells in modulating chronic inflammation and osteonecrosis

Abstract

Osteonecrosis occurs when, under continuous stimulation by adverse factors such as glucocorticoids or alcohol, the death of local bone and marrow cells leads to abnormal osteoimmune function. This creates a chronic inflammatory microenvironment, which interferes with bone regeneration and repair. In a variety of bone tissue diseases, innate immune cells and adaptive immune cells interact with bone cells, and their effects on bone metabolic homeostasis have attracted more and more attention, thus developing into a new discipline - osteoimmunology. Immune cells are the most important regulator of inflammation, and osteoimmune disorder may be an important cause of osteonecrosis. Elucidating the chronic inflammatory microenvironment regulated by abnormal osteoimmune may help develop potential treatments for osteonecrosis. This review summarizes the inflammatory regulation of bone immunity in osteonecrosis, explains the pathophysiological mechanism of osteonecrosis from the perspective of osteoimmunology, and provides new ideas for the treatment of osteonecrosis.

Keywords: bone regeneration; cytokines; immune cells; inflammation; osteoimmunology; osteonecrosis.

Figure 1

Inflammation initiates bone repair. When bone injury occurs, damage-associated molecular patterns (DAMPs) are recognized by pattern recognition receptors (PRRs) expressed on the surface of local cells. These cells are activated to release inflammatory factors that recruit immune cells, which can phagocytose bone fragments and cell debris or produce pro-inflammatory factors to recruit mesenchymal stem cells and initiate osteogenesis and angiogenesis. The overall result is resolution of inflammation and new bone tissue. Abbreviations: CCL2, C-C motif chemokine ligand 2; ECM, extracellular matrix; IL-1, interleukin 1; IL-6, interleukin 6; PMN, polymorphonuclear leukocytes; SDF1, stromal cell-derived factor 1; TNF-α, tumor necrosis factor–alpha.

Figure 2

Uncontrolled inflammation promotes osteonecrosis. A controlled inflammatory response to bone injury activates immune cells to remove damaged tissue, then returns to baseline levels conducive to bone regeneration. Excessive inflammation maintains high levels of inflammatory factors that further destroy bone, while an insufficient inflammatory response fails to clear immune-activating factors. Either inflammatory disorder eventually leads to chronic inflammation and osteonecrosis. The green curve represents the change in the inflammatory level of controlled inflammation over time, while the orange and blue curves represent the inflammation level of excessive inflammation and insufficient inflammation, respectively. Abbreviations: IL-6, interleukin 6; ROS, reactive oxygen species; TNF-a, tumor necrosis factor–alpha.

Figure 3

Innate immune cells in osteonecrosis. Neutrophils cause microvascular blockage and osteolysis by secreting, respectively, NETs and pro-inflammatory factors, resulting in osteonecrosis of the femoral head. Activation of the TLR4/MyD88/NF- κB and JAK/STAT1 pathways polarizes macrophages to the M1 phenotype, and they secrete inflammatory factors TNF-α, IL-1β and IL-6 to promote osteoclast differentiation and osteolysis. In osteonecrosis, macrophage polarization to the M2 phenotype is blocked, further impairing bone repair. DCs can differentiate into osteoclasts and participate in bone remodeling under the stimulation of RANKL secreted by T cells. DCs present processed antigens and secrete inflammatory factors that affect T cell differentiation. Abbreviations: DCs, dendritic cells; IL-1β, interleukin 1 beta; IL-4, interleukin 4; IL-6, interleukin 6; IL-10, interleukin 10; IL-12 p70, interleukin 12 p70; IL-17, interleukin 17; M0, Macrophages; M1, classically activated macrophages; M2, alternatively activated macrophages; NETs, neutrophil extracellular traps; RANKL, receptor activator of nuclear factor kappa-B ligand; TGF-β, tumor growth factor beta; TNF-α, tumor necrosis factor–alpha.

Figure 4

Adaptive immune cells in osteonecrosis. T cells can differentiate into the T helper cells (Th), cytotoxic T lymphocytes (CTLs) and regulatory T cell (Tregs) subtypes, which secrete various cytokines to influence chronic inflammation and osteoclast differentiation in different ways. Pre-B-cells and immature B cells are found only in bone marrow, while Bregs, plasma cells and activated B cells are recruited into osteonecrosis tissue. Activated B cells affect differentiation of T cell subtypes by presenting processed antigens and secrete RANKL to promote osteoclast differentiation. Bregs, plasma cells, Pre-B-cells and immature B cells secrete IL-10 and OPG respectively to inhibit osteoclast differentiation. Abbreviations: Bregs, regulatory B cells; CTLA-4, cytotoxic T lymphocyte-associated protein 4; IL-4, interleukin 4; IL-9, interleukin 9; IL-10, interleukin 10; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa-B ligand; TGF-β, tumor growth factor beta.