CX3CL1 promotes M1 macrophage polarization and osteoclast differentiation through NF-κB signaling pathway in ankylosing spondylitis in vitro

Abstract

Background Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. Methods The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. Results The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. Conclusions The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.

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“… 47 , 48 CX3CL1 is reported to promote M1 macrophage polarization in ankylosing spondylitis. 49 These studies suggested that cytokines as TIMP1, TIMP2, CCL3, IL9, and CX3CL1 in ESIONPs@EXO promoted M1 macrophage polarization. Meanwhile, CX3CL1 deficiency is reported to suppress cell ferroptosis via increasing the levels of GSH and GPX4.…”

“…Both TIMP1 and TIMP2 are natural inhibitors of the matrix metalloproteinases (MMPs), and the deficiency of TIMP1 and TIMP2 promotes angiogenic M2 macrophage polarization. , CCL3 is reported to induce M1 macrophage polarization in necrotizing enterocolitis . IL-9 is a cytokine with potent proinflammatory properties and can stimulate antitumor M1 macrophages polarization in lung cancer. , CX3CL1 is reported to promote M1 macrophage polarization in ankylosing spondylitis . These studies suggested that cytokines as TIMP1, TIMP2, CCL3, IL9, and CX3CL1 in ESIONPs@EXO promoted M1 macrophage polarization.…”

Unraveling New Therapeutic Targets in Ankylosing Spondylitis: Multi-Omics Mendelian Randomization on Immune Cells, Metabolites, and Inflammation Proteins

“…This cytokine secretion ampli es systemic in ammation and facilitates the interaction with Innate Lymphoid Cell 3 (ILC3), implicating a vital link between gut immunity and systemic in ammatory pathways integral to AS pathogenesis (27)(28)(29). Additionally, the CX3CL1/CX3CR1 axis is implicated in chronic pain and bone resorption, suggesting a broader role in mediating the gut-joint in ammatory axis characteristic of AS (29)(30)(31)(32)(33). Furthermore, the activation and antigen-presenting capabilities of CD62L-CD86 + myeloid DCs are central to orchestrating an immune response that favors AS development.…”

Network Pharmacology and Molecular Modeling Techniques in Unraveling the Underlying Mechanism of Citri Reticulatae Pericarpium aganist Type 2 Diabetic Osteoporosis

“…It also regulates the effects on the bones through multiple pathways, and in the ESR 1-Keap 1-Nrf 2 axis, ESR1 can interact with Nrf2 to promote osteogenic differentiation [ 45 ]; it can also affect the Wnt/β-catenin pathway and thus exert its influence on bone mineralization [ 46 ]. Moreover, there is evidence that several other targets also play important roles in osteogenic differentiation [ 47 , 48 , 49 , 50 , 51 ]. Thus, some theoretical basis can be established for the utilization of these core targets in the treatment of T2DOP.…”