Dissecting the Mechanical Profiles and the Underlying Mechanoimmunological Mechanism of Macrophages

剖析巨噬细胞力学特性及潜在的力学-免疫学机理

Yizebang XUE (薛以泽邦)

11653006

博士

生物医药（Biomedical Sciences）

工学博士

唐斌

Chunming WANG (王春明)

2021-11-24

2021-12-31

澳门大学

澳门

Nowadays, harness macrophage multifunctions for mitigating inflammatory response, promoting tissue regeneration and guiding biomaterials design is promising. The mechanism of chemokine & cytokine-induced polarization has been widely studied. However, the relationship between polarization and physical cues, such as extracellular matrix (ECM) topography and mechanical properties, is poorly understood. To uncover macrophages’ mechanobiological profiles, the whole thesis includes four parts: 1. Verify the mechanical modulation via tunable substrates; 2. Investigate the cell mechanics of single macrophages at various phenotypic states, and correlated secretion patterns; 3. Determine the interlock of cell stiffness and immune response. First, we selected osteoarthritis as the target pathological case to validate macrophage’s mechanobiology from the substrate stiffness. Mixing a bio-inert material Eucommia Ulmoides Gum (EUG) and a commercial biocompatible material polycaprolactone (PCL), the fibrous scaffolds were fabricated to mimic the deteriorate articular cartilage. It is turn out that the damaged ECM may induce persistent articular inflammation. In the next step, we explore the mechanoimmunology at a single-cell scale rather than the external substrate scale. Cell mechanical properties would straight determine the cellular deformation, which initiates the subsequent mechanotransduction. We performed the AFM-conditional rate-jump method to quantify the cell stiffness at various phenotypes. We found inflammation would enhance the cell stiffness obviously; anti-inflammatory activation will soften cell stiffness. Furthermore, the generation of pro-inflammatory cytokines in activated macrophages positively correlated with the final elastic modulus. When macrophages recognize dangerous signals, they convey the bacterial signals through the NLR/TLR- NF-κB- MAPK/PI3K- actin organization routes. Finally, we evaluated the role of cell stiffness in regulating the immune response. As expected, applying actin destabilizers reduced cell stiffness and the associated immunological sensitivity. Besides, the capacity of exerting immune response positively relates to macrophage’s cell stiffness. Cell stiffness variation is not simply a consequence of immune response, but also a unique input to support the cytokine secretion. These findings refer to the distribution and activation preference of native macrophages in several pathological microenvironments. The in-depth knowledge of mechanoimmunology will provide new sights for pathogenesis, biomaterials design and clinic application.

macrophag immune response cell mechanics mechanobiology

巨噬细胞 免疫反应 细胞力学 力学生物学

英语

联合培养

南方科技大学

Yizebang XUE . Dissecting the Mechanical Profiles and the Underlying Mechanoimmunological Mechanism of Macrophages[D]. 澳门. 澳门大学,2021.