fimmu-15-1362012-g002

Credit:DOI: 10.3389/fimmu.2024.1362012.

Scatter and funnel plots of Mendelian randomization (MR) analyses for granulocyte colony-stimulating factor (G-CSF) and macrophage inflammatory protein-1 alpha (MIP-1A) in patients with knee osteoarthritis (KOA). (A) The exposure is G-CSF and outcome is KOA. (B) The exposure is KOA and outcome is MIP-1A. (C, D) Funnel plots show the inverse variance weighted MR estimate of each cytokine single-nucleotide polymorphism (SNP) with KOA versus 1/standard error (1/SEIV).

Knee osteoarthritis (KOA) is a chronic degenerative disease characterized by degradation of articular cartilage, sclerosis of subchondral bone, and inflammation of periarticular soft tissues [1]. As important immune cells, mast cells (MCs) complete their specific differentiation and maturation under the influence of the tissue microenvironment, and have been widely studied in the context of allergy, intrinsic and acquired immunity. Obesity is one of the independent risk factors for KOA, and with the progress of society and the improvement of living conditions, the number of obese people has been increasing, which has led to an increase in the number of people with KOA. Studies have shown that the incidence of KOA in obese patients ranges from 12% to 43%, and the incidence of KOA in obese patients is higher than that in normal-weight people in all age groups [2]. As highly heterogeneous cells in adipose tissue, MCs exist in large numbers in adipose tissue and are involved in the formation, metabolism, and biological functions of fat. In recent years, the physiological and pathological roles of MCs in obese adipose tissue have attracted extensive attention from academia.

MCs are derived from CD13+, CD34+, CD117+ bone marrow pluripotent hematopoietic progenitor cells with a wide tissue distribution and can survive in tissues for months. Mature MCs express a variety of receptors, such as pattern recognition receptors, including Toll-like receptors (TLR) and NOD-like receptors; cytokine receptors, including interleukin (IL)-1, IL-33, interferon gamma; Fc receptors, including FcεRⅠ and FcγR Ⅰ. The binding of these receptors to the corresponding ligands can affect the development, proliferation and survival of MCs and induce MCs activation. The main pathways of MCs activation are immunoglobulin E (IgE)-dependent and non-dependent approaches. Although, IgE-dependent signaling is the main pathway for MCs activation, the IgE-non-dependent pathway has also been found to play a key role in the pathophysiology of various inflammatory diseases. Activated MCs can affect OA by the following mechanisms: (1) release of cytokines and chemokines to attract other immune cells; (2) release of soluble mediators and enzymes to cause pain in OA.Activation of MCs induces the release of preformed mediators from their particles or de novo synthesis and release of mediators. De novo synthesis mediators include histamine and trypsin-like enzymes. De novo synthesis and release of mediators include the lipid mediator prostaglandin D2, cytokines IL-33, IL-6, tumor necrosis factor-α (TNF-α), and chemokines such as monocyte chemotactic protein-1 (MCP-1). In the absence of typical degranulation, MCs can play different roles during pathophysiological responses such as inflammation, tissue injury, and inflammatory pain by selectively releasing these highly active biological factors [3].

MCs and adipose tissue interact with each other. Gurung et al [4] showed that the number of MCs per unit area in the subcutaneous adipose tissue of patients with metabolic syndrome was 4.5 times higher than that of the normal population, and the activation of MCs was significantly increased with the increase in the number of MCs. Takata et al [5] indicated that the increase in the number of MCs may lead to elevated synovial basic fibroblast growth factor expression in obese KOA patients, which was associated with the severity of KOA.  In addition, when excessive accumulation of fat disrupts the normal endocrine pattern of adipose tissue, resulting in an imbalance of adipokine secretion, activated and degranulated MCs in adipose tissue may release a large number of pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, and MCP-1, into the extracellular space to recruit immune cells such as macrophages and neutrophils [6].

These studies have illustrated that the number of MCs is increased in obese adipose tissue and activation of MCs can promote adipose tissue inflammation.

Reference

  1. Zhang, J., Li, K., & Qiu, X. (2024). Exploring causal correlations between inflammatory cytokines and knee osteoarthritis: a two-sample Mendelian randomization. Frontiers in immunology, 15, 1362012.

  2. Batushansky, A., Zhu, S., Komaravolu, R. K., South, S., Mehta-D'souza, P., & Griffin, T. M. (2022). Fundamentals of OA. An initiative of Osteoarthritis and Cartilage. Obesity and metabolic factors in OA. Osteoarthritis and cartilage, 30(4), 501–515.

  3. Elieh Ali Komi, D., Wöhrl, S., & Bielory, L. (2020). Mast Cell Biology at Molecular Level: a Comprehensive Review. Clinical reviews in allergy & immunology, 58(3), 342–365.

  4. Gurung, P., Moussa, K., Adams-Huet, B., Devaraj, S., & Jialal, I. (2019). Increased mast cell abundance in adipose tissue of metabolic syndrome: relevance to the proinflammatory state and increased adipose tissue fibrosis. American journal of physiology. Endocrinology and metabolism, 316(3), E504–E509.

  5. Takata, K., Uchida, K., Takano, S., Mukai, M., Inoue, G., Sekiguchi, H., Aikawa, J., Miyagi, M., Iwase, D., & Takaso, M. (2021). Possible Regulation of bFGF Expression by Mast Cells in Osteoarthritis Patients with Obesity: A Cross-Sectional Study. Diabetes, metabolic syndrome and obesity : targets and therapy, 14, 3291–3297.

  6. Elieh Ali Komi, D., Shafaghat, F., & Christian, M. (2020). Crosstalk Between Mast Cells and Adipocytes in Physiologic and Pathologic Conditions. Clinical reviews in allergy & immunology, 58(3), 388–400.