Browsing by Subject "immunobiology"

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  • Guenther, Carla (Helsingin yliopisto, 2020)
    Our health is protected by the immune system, which maintains a carefully regulated balance between inflammation and immune suppression. To mediate homeostasis and inflammation, leukocytes continuously patrol the body and therefore operate in a dynamic mechanical landscape. Mechanical information is transduced into the cell via different proteins, including adhesion receptors called β2-integrins. These receptors mediate essential leukocyte processes, including phagocytosis, immune cell trafficking, adhesion under shear flow conditions of the blood stream and immunological synapse formation between antigen presenting cells and T-cells. However, β2-integrins can also restrict inflammatory processes, such as macrophage Toll-like receptor signalling and cytokine expression, as well as dendritic cell maturation and migration. The precise signalling pathways involved in β2-integrin-mediated leukocyte regulation are not yet fully unravelled. β2-integrin activity is regulated via conformational changes. β2-integrin conformational changes are mediated by interactions with cytoplasmic proteins, such as talin, filamin A and kindlin-3. Talin, filamin A and kindlin-3 are sensitive to mechanical forces and respond by changing their conformation. However, the precise roles of these two proteins in regulating β2-integrin mediated immune processes, especially in response to force, have not yet been fully investigated. The aim of this doctoral thesis was to study molecular mechanisms involved in β2-integrin-mediated leukocyte mechanotransduction and immune responses. We investigated the role of filamin A in β2-integrin-mediated primary neutrophil and T-cell adhesive functions using conditional filamin A knockout mice. In neutrophils, filamin A restricts β2-integrin mediated cell spreading and static adhesion. Furthermore, filamin A was found to inhibit neutrophil oxidative burst, but it was required for proper formation of neutrophil extracellular traps. In T-cells, filamin A restricts F-actin content in cells spreading on integrin ligands. Interestingly, filamin A plays a different role in T-cell adhesion than in neutrophils, as it is required for optimal adhesion under shear flow conditions, and for the generation of integrin-mediated traction forces. Furthermore, filamin A is necessary for T-cell homing in vivo and for T-cell trafficking to sites of inflammation. Together the studies therefore revealed a dual role for the mechanosensitive integrin-binding protein filamin A in regulating leukocyte adhesive processes. In dendritic cells, β2-integrins have previously been shown to regulate gene expression, and to restrict cell maturation, migration and dendritic cell-mediated T-cell activation. Here, we used a β2-integrin TTT/AAA knock-in (KI) mouse model, where the β2-integrins/kindlin-3 interaction has been disrupted, which leads to expressed but dysfunctional integrins. The aim of these studies was to identify integrin-mediated signalling pathways regulating the mature dendritic cell phenotype. In our studies, we found that the mechanoresponsive MRTF-A/SRF pathway is downstream of β2-integrins in dendritic cells. Furthermore, this pathway regulates cytoskeletal gene expression, which governs the ability of dendritic cells to adhere and to generate traction forces, but not dendritic cell 3D migration. We subsequently identified novel mechanotransductional mechanisms involved in integrin-mediated dendritic cell programming and function. We discovered a β2-integrin/actin/lamin link in dendritic cells that regulates global histone methylation in these cells, as well as chromatin accessibility and gene expression. Interestingly, targeting this mechanical link leads to a similar mature dendritic cell phenotype as that caused by abolishing β2-integrin function, and can be used to induce better dendritic cell-mediated tumour rejection in vivo. Taken together, these studies outline several β2-integrin mediated leukocyte mechanotransduction pathways, which we demonstrate are relevant for immune system function in vivo. The results highlight the importance of considering and studying how mechanical forces and information impact immune system function. This is especially important in diseases such as cancer and during aging where the mechanical properties of tissues change over time.