Understanding Mechanosensation: More Than Push and Pull

It’s fair to say that when we typically think about how cells sense and respond to their environment, we imagine chemical signals and molecular interactions. Membrane proteins like ion channels are located at the interface between external and intracellular compartments, thus mediating external cues into cellular signaling. Ion channels and other membrane proteins are known to initiate cellular signaling in response to various cues, like specific ligands and electrical events. Less familiar is the responsiveness of several ion channels to mechanical forces.

Mechanosensation, the process by which cells detect and respond to mechanical stimuli through dedicated membrane proteins, is a growing field that’s revealing a number of critical – and sometimes unexpected – roles in various biology, from immunology to cancer progression and more.

What is Mechanosensation?

In short, mechanosensation is about converting mechanical forces into cellular signals. This conversion is primarily mediated by mechanosensitive ion channels, such as those from the transient receptor potential V (TRPV) and Piezo families. These channels are key to a whole spectrum of cellular functions.

Mechanosensation in Immunity and Inflammation

One of the fascinating and perhaps most unexpected aspects of mechanosensation is its proposed role in immunology. Macrophage, a major player in the innate immune response, have recently been shown to rely on the mechanosensitive ion channel Piezo1 for sensing the microenvironmental tissue stiffness associated with numerous diseases. Mechano-activation of macrophage’s Piezo1 channels leads to macrophage polarization (1), which is essential for its proper function. Another recent study demonstrated a role for macrophage TRPV4 ion channel in mediating the immune response in a model of inflammatory lung disease. The researchers revealed that the initiation of the whole process depends on TRPV4 mechanosensitivity to the pathophysiological stiffness of the extracellular matrix (Figure 1) (2). This connection between mechanical stimuli and immune function has given rise to the concept of mechanoimmunology (3).

Figure 1. Matrix mechanical signal transduction through TRPV4 modulates the LPS signal through MAPK switching. A. In the presence of a sub-threshold mechanical signal, as seen in normal lung, TRPV4 does not

influence the LPS/TLR4 signal, which results in limiting the phagocytic response to LPS, thereby maintaining lung homeostasis. B. In the presence of an above threshold mechanical signal, as seen with lung stiffening during injury, TRPV4 influences the LPS/TLR4 signal. We have previously published that TRPV4 regulates the stiffness-dependent responses of increased macrophage phagocytosis, and cytokine secretion in response to LPS. We now show a molecular switch from JNK activation to predominantly p38 activation, which results in abrogation of enhanced DUSP1 expression. DUSP1 regulates the MAPK molecular switch by deactivating JNK resulting in enhanced bacterial clearance, inhibiting pro-inflammatory cytokine secretion, and thereby ameliorating lung injury/ARDS. From Scheraga et al. (2021) (2)

Cancer and Mechanosensation

We also see mechanosensation with a role in cancer progression. TRPV2 and TRPV4 ion channels are notable here for their involvement in tumorigenesis (4). Changes in tissue stiffness, a hallmark of pathological tissue like cancer, activate these channels and promote cancer cell proliferation, migration, and invasion. For instance, TRPV2 activation in cancer cells has been linked to increased metastatic potential and poor prognosis​ (5). Although this is still in the zone of basic research, the mechanotransduction pathway could very well hold potential as therapeutic target, potentially limiting the spread of cancer by modulating the mechanical environment of tumors.

Mechanosensation in Cardiovascular Research

Beyond immunity and cancer, mechanosensation has a somewhat more expected role to play in cardiovascular homeostasis and sensory perception. Mechanosensitive ion channels like TRPV4 help to detect and respond to mechanical stimuli in those tissues under dynamic load, such as the heart and lungs. These channels help regulating vascular tone, which in turn contributes to modulation of cardiovascular associated processes​ (6).

Alomone Labs’ Antibodies for Mechanosensation Research

If you’re trying to understand the complexities of mechanosensation, we’ve developed a collection of conjugated primary antibodies here at Alomone Labs that specifically target the extracellular domains of TRPV4, Piezo1 and TRPV2 channels. These antibodies are ideal for live cell imaging applications, such as flow cytometry, and are available in FITC conjugation versions, with alternatives in PE or APC conjugations.

Below, you can see these antibodies in action in a multicolor flow cytometry assay (Figure 2).

Figure 2. Multicolor flow cytometry for cell surface markers in mouse J774 macrophages. This assays used Anti-TRPV4 (extracellular)-PE Antibody (#ACC-124-PE), Anti-Piezo1 (extracellular)-APC Antibody (#APC-087-APC) and Anti-TRPV2 (VRL1) (extracellular)-FITC Antibody (#ACC-039-F).

A Final Push

Mechanosensation is a vital, yet often overlooked, aspect of cellular physiology. It bridges the gap between mechanical forces and cellular signaling to influence processes as diverse as immune responses, cancer progression and cardiovascular functions.

We believe our new antibody collection, developed and validated in-house, offers you a set of valuable tools for your research that can help uncover new insights and potential therapeutic avenues in mechanosensation-related disorders.

References

1. H. Atcha, A. Jairaman, J. R. Holt, V. S. Meli, R. R. Nagalla, P. K. Veerasubramanian, K. T. Brumm, H. E. Lim, S. Othy, M. D. Cahalan, M. M. Pathak, W. F. Liu, Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Nat Commun 12, 3256 (2021). DOI: https://doi.org/10.1038/s41467-021-23482-5.
2. R. G. Scheraga, S. Abraham, L. M. Grove, B. D. Southern, J. F. Crish, A. Perelas, C. McDonald, K. Asosingh, J. D. Hasday, M. A. Olman, TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching. J Immunol 204, 1310–1321 (2020). DOI: https://doi.org/10.4049/jimmunol.1901033.
3. S. V. Pageon, M. A. Govendir, D. Kempe, M. Biro, Mechanoimmunology: molecular-scale forces govern immune cell functions. Mol Biol Cell 29, 1919–1926 (2018). DOI: https://doi.org/10.1091/mbc.E18-02-0120.
4. T. Kärki, S. Tojkander, TRPV Protein Family-From Mechanosensing to Cancer Invasion. Biomolecules 11, 1019 (2021). DOI: https://doi.org/10.3390/biom11071019.
5. K. F. Shoji, E. Bayet, S. Leverrier‐Penna, D. Le Devedec, A. Mallavialle, S. Marionneau‐Lambot, F. Rambow, R. Perret, A. Joussaume, R. Viel, A. Fautrel, A. Khammari, B. Constantin, S. Tartare‐Deckert, A. Penna, The mechanosensitive TRPV2 calcium channel promotes human melanoma invasiveness and metastatic potential. EMBO Rep 24, e55069 (2023). DOI: https://doi.org/10.15252/embr.202255069.
6. L. Liu, M. Guo, X. Lv, Z. Wang, J. Yang, Y. Li, F. Yu, X. Wen, L. Feng, T. Zhou, Role of Transient Receptor Potential Vanilloid 4 in Vascular Function. Front Mol Biosci 8, 677661 (2021). DOI: https://doi.org/10.3389/fmolb.2021.677661.