NEWS AND VIEWS

Pressure regulates immune-cell function

Immune cells called monocytes enter the lung during infection. Whether they help to launch a defence response is affected by the pressure encountered there, which is sensed by an ion channel called PIEZO1.
Sarah R. Walmsley is at the Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Contact

Search for this author in:

An effective immune response to general signs of infection, regulated by the branch of the immune system called innate immunity, is essential for the removal of unwanted bacteria. Such a response should then end when the infection is over — dampening and blocking any unwanted inflammatory response. The processes that determine whether inflammation is effective or dysfunctional are of considerable therapeutic interest, given the lack of available strategies to target harmful inflammation while preserving beneficial host defences. Efforts to understand how immune cells respond to inflammation have, in turn, focused attention on immune regulatory processes. These include processes involved in sensing the damage associated with infection1, as well as those needed to recognize other infection-related changes, such as alterations in nutrient2 or oxygen levels3,4. Writing in Nature, Solis et al.5 reveal that mechanical cues generated in the mouse lung are sensed by immune cells and are crucial regulators of an immune response.

The immune system’s myeloid cells — a group that includes macrophages and monocytes — are exposed to a range of physical forces, for example those encountered when leaving blood vessels to enter tissues6. Cycles of mechanical force occur in organs such as the lung, in which tissues are compressed during breathing7. These forces are themselves subject to change in disease states; for example, when tissue swells during an inflammatory response. Solis and colleagues report that macrophages and monocytes can respond to mechanical cues that are perceived through a mechanosensory ion channel called PIEZO1 that is located on their cell surface.

To understand whether the exposure of myeloid cells to mechanical forces could directly regulate immune-cell function, the authors generated mice that lacked PIEZO1 in myeloid cells. Using an in vitro system, the authors subjected immune cells to cycles of pressure change, mimicking those encountered in the lung, called cyclical hydrostatic pressure. The authors compared wild-type and PIEZO1-deficient macrophages and monocytes, which revealed that cyclical hydrostatic pressure induces a pro-inflammatory gene-expression profile in wild-type cells that depends on PIEZO1. This expression profile included genes that are controlled by the transcription-factor protein HIF1α, a key regulator of gene expression that is needed for myeloid cells to function and survive810. Interestingly, this pro-inflammatory gene-expression response was unaffected by the magnitude of the pressure encountered.

To understand the mechanisms driving this transcriptional response, the authors studied macrophages that were deficient in HIF1α. They found that the cells were unable to mount a pro-inflammatory gene-expression response to cyclical hydrostatic pressure. The authors reveal that subjecting wild-type cells to this type of pressure in the in vitro system drives an influx of calcium ions into cells through the PIEZO1 channel, which results in accumulation of HIF1α (Fig. 1). This PIEZO1-mediated boost to HIF1α required the production of the hormone endothelin 1, which acts in a signalling pathway that stabilizes HIF1α in cells11,12. Endothelin 1 is secreted by cells and acts by binding to its receptor either on the cell that secreted it or on a neighbouring cell.

Figure 1 | Immune cells in the lung respond to pressure by triggering a defence response. By studying mouse immune cells grown in vitro and mouse models of bacterial infection of the lung, Solis et al.5 investigated how immune cells called monocytes respond to the cycles of pressure that occur during breathing. They focused on structures in the lung called alveoli, which are the ‘air sacs’ of this organ. The authors report that pressure activates a mechanosensory receptor protein called PIEZO1 on monocytes, triggering an influx of calcium ions (Ca2+). This leads to the expression of the hormone endothelin 1 (ET1), which is secreted from the cell. When it binds to its receptor, this stimulates a signalling pathway that stabilizes the protein HIFα, which drives the expression of pro-inflammatory genes. One such gene encodes the protein CXCL2, which is secreted from the cell. CXCL2 attracts a type of immune cell called a neutrophil, which enters the lung from the bloodstream, whereupon it can target bacteria that are present.

To test the role of PIEZO1-mediated signalling in host defences, Solis and colleagues used a mouse model of pneumonia in which infection is caused by the bacterium Pseudomonas aeruginosa. Compared with wild-type mice, animals that were engineered to lack PIEZO1 in myeloid cells had fewer immune cells called neutrophils in the lung tissues, and lower levels of pro-inflammatory immune-signalling molecules in the lungs, such as endothelin 1. They also had lower levels of the protein CXCL2, which attracts neutrophils. Such mice had higher levels of bacteria in their lungs and greater bacterial spread to the liver compared with wild-type mice.

The authors report that production of endothelin 1 was not affected if PIEZO1 was depleted in mouse macrophages found in a lung structure called the alveolus, or if the ion channel was depleted in dendritic cells, which are another type of lung immune cell. However, depleting monocytes caused a reduction in the levels of endothelin 1, implicating the cells as a source of this hormone. The authors confirmed that PIEZO1-dependent production of endothelin 1 has a key role in defences against infection, by showing that administering endothelin 1 to mice lacking PIEZO1 in myeloid cells reduced the burden of unwanted bacteria, when compared with the bacterial burden in such animals that did not receive endothelin 1. Solis and colleagues’ work is consistent with a model in which PIEZO1-mediated mechanosensation by monocytes in the lung activates these cells to produce endothelin 1, driving a rise in the level of HIF1α and a pro-inflammatory gene-expression profile. In turn, that results in the recruitment of neutrophils, which help to get rid of unwanted bacteria.

These observations raise key questions regarding the broader relevance of PIEZO1 signalling in other diseases associated with altered lung mechanics, such as pulmonary fibrosis. This condition is characterized by high levels of immune cells in the lungs, a reduction in lung elasticity and restricted airflow. Solis and colleagues report that mice lacking PIEZO1 in myeloid cells are protected from lung damage in a mouse model of pulmonary fibrosis, which suggests that PIEZO1-regulated immune-cell function might have a role in human disease. This should be an area of focus as these studies continue.

Understanding how signals are integrated to mediate an effective immune response will require a greater depth of understanding than we have now. This is relevant in this case because immune cells move between different compartments in the lung, and are thus exposed to a range of environmental cues. Although PIEZO1 can promote a pro-inflammatory response that boosts the removal of unwanted bacteria, loss of this ion channel can also be beneficial, given that it can protect from the damaging inflammation associated with the mouse model of pulmonary fibrosis. Dissecting the regulatory steps that maintain a balanced, effective immune response will be necessary for exploring therapeutic avenues to target mechanosensory pathways during lung inflammation.

Nature 573, 41-42 (2019)

References

  1. 1.

    Huang, C. & Niethammer, P. Immunity 48, 1006–1013 (2018).

  2. 2.

    O’Neill, L. A. J. & Hardie, D. G. Nature 493, 346–355 (2013).

  3. 3.

    Sadiku, P. & Walmsley, S. R. EMBO Rep. 20, e47388 (2019).

  4. 4.

    Taylor, C. T. & Colgan, S. P. Nature Rev. Immunol. 17, 774–785 (2017).

  5. 5.

    Solis, A. G. et al. Nature 573, 69–74 (2019).

  6. 6.

    Begandt, D., Thome, S., Sperandio, M. & Walzog, B. J. Leukoc. Biol. 102, 699–709 (2017).

  7. 7.

    Mead, J. & Whittenberger, J. L. J. Appl. Physiol. 5, 779–796 (1953).

  8. 8.

    Kaelin, W. G. Jr & Ratcliffe, P. J. Mol. Cell 30, 393–402 (2008).

  9. 9.

    Lin, N. & Simon, M. C. J. Clin. Invest. 126, 3661–3671 (2016).

  10. 10.

    Palazon, A., Goldrath, A. W., Nizet, V. & Johnson, R. S. Immunity 41, 518–528 (2014).

  11. 11.

    Liu, Y. V. et al. J. Biol. Chem. 282, 37064–37073 (2007).

  12. 12.

    Li, M. et al. FEBS Lett. 586, 3888–3893 (2012).

Download references

Nature Briefing

An essential round-up of science news, opinion and analysis, delivered to your inbox every weekday.