The Immune Cell, the Neutrophil – the Good, the Bad, or the Ugly?

By Kathryn Higgins

Throughout our lifetime our bodies sustain infections and injuries, and the body deals with them by mediating an inflammatory response. This happens by cells within our blood entering the site of infection or injury and carrying out multiple biological reactions. These reactions can kill the microorganism that has caused the infection, but also heal at the site of injury, and hence resolve inflammation. These blood cells are collectively called white blood cells or leukocytes, and there is one in particular, named the neutrophil, which not only helps to resolve inflammation but can also exacerbate the condition further. This has resulted in the neutrophil having a reputation for being both ‘good’ and ‘bad’ in inflammatory conditions.

The reputation of the neutrophil is influenced by many molecules that are released from other cell types during inflammation. These molecules influence the activity of the neutrophil in various ways, either stimulating the cell so inflammation can be resolved or inhibiting a particular function the cell has. The influence of these molecules determines whether the neutrophil is able to carry out its functions efficiently or whether the inflammatory condition will be aggravated further. The biological activities of neutrophils therefore need to be understood to comprehend how they function and how these roles can be modulated to determine what effect this has during an inflammatory response.

Neutrophils form part of the body’s innate immunity which involves a series of defence mechanisms that protect the host from infection and form the early barriers to infectious diseases without relying on the production and expansion of antibodies that form the adaptive immune response. When an infection occurs, the innate immune response is triggered to rapidly detect and destroy the infection. Neutrophils are one of the first blood cells to respond to infection and are recruited from the circulating blood into the tissue by molecules called chemoattractants1. These molecules, released from cells at the site of infection and also from the microorganism, also known as a pathogen, provide a chemical gradient for neutrophils to migrate along, with the highest concentration of these chemoattractants situated at the site of infection, so the cells are led directly to the infected site. Once in the tissue the lifespan of the cell is increased to approximately 1-2 days as opposed to 6-10 hours in the circulation. This is to lengthen the amount of time neutrophils have to carry out their functions and resolve inflammation.

A vital part of the innate immune response is the ability of the neutrophils to engulf pathogens and aid the resolution of infection. This process is called phagocytosis and classifies the neutrophil as a phagocyte, so called after the Greek for ‘devouring cells’. When the neutrophil has entered the infected site and detected the pathogen, the outer membrane of the neutrophil surrounds the pathogen to engulf it and so the pathogen becomes taken up into the cell. Neutrophils contain many granules and these are packed with lots of toxic reagents. Upon engulfment these granules fuse with the pathogen and release their toxic contents, by a process called degranulation, and these contents assist in the killing of the pathogen2.

In addition to degranulation, neutrophils can also kill pathogens by oxidative mechanisms, so called because molecular oxygen is required. This involves a process named the respiratory burst and it is the major mechanism by which neutrophils kill and digest pathogens. During the engulfment of a pathogen into the neutrophil, molecular oxygen is also rapidly taken up. The oxygen is then converted, by a series of chemical reactions, into several toxic compounds such as hydrogen peroxide. Further chemical reactions may occur producing even more potent substances3 and when the pathogen becomes exposed to these various toxic oxygen metabolites the pathogen is digested and destroyed within the cell.

Neutrophils have also been shown to kill pathogens outside of the cell, i.e. extracellularly, rather than engulfing them. This occurs by neutrophils releasing web-like structures of genetic material, called neutrophil extracellular traps (NETs)4. These NETs are composed of fibres that trap pathogens, and have been proposed to contain high concentrations of anti-microbial compounds, such as those contained within their granules, to kill pathogens and prevent the spread of infection. Some bacteria, however, have evolved to counteract being killed by NETs by producing substances that degrade the genetic material that make up NETs, such as Streptococcus pneumoniae5, which is known to be the common cause of pneumonia.

Once the pathogens have been dealt with, and to completely resolve inflammation, neutrophils need to be cleared from the tissue. If the cells do not become removed then all their toxic contents, such as the granule contents and oxygen metabolites that kill pathogens, may leak out of the cell and damage surrounding cells and tissues, which will only make the inflammatory condition worse. For removal, neutrophils firstly need to die. This is by a programmed type of cell death termed apoptosis6 which ensures that the cellular membrane remains intact so these toxic contents are retained within the cell and cannot be released. During this cell death a fatty (lipid) molecule called phosphatidylserine is flipped to the outer surface7. This lipid acts as a signal for tissue macrophages to target the dead neutrophil. Tissue macrophages are another class of white blood cell with a vital role of recognising apoptotic cells. Once the signal has been recognised, the neutrophil itself is then engulfed by the macrophage and cleared from the tissue. It is essential that these apoptotic cells are removed efficiently from the tissue because a delay in their clearance can also increase the chance of their intact membranes becoming leaky.

Apoptosis is therefore a process which needs to be tightly regulated to ensure inflammation is resolved efficiently. If cell death is stimulated too early then the number of functional neutrophils in the tissue is reduced. This would limit the hosts’ ability to fight infection and resolve inflammation. For example, some infections induce neutrophil apoptosis, such as the influenza A virus8 and the Pseudomonas aeruginosa bacterium9 to favour their own survival. In contrast to this, if apoptosis is delayed, as seen with the inflammatory joint disorder rheumatoid arthritis10, the number of circulating cells in the tissue increases, toxic contents may then be released from the cells, and surrounding tissue would be damaged potentiating inflammation further. This contrasting effect of the neutrophil is often referred to as the ‘double-edged sword’ effect, i.e. can be both ‘good’ and ‘bad’ during the inflammatory process, with the damaging effects of the neutrophil quickly out-weighing the benefits. Although neutrophils may often appear to be the ‘bad’ guy in certain inflammatory conditions this is typically due to the influence of other molecules released from surrounding cells. Without this influence the primary aim of the neutrophil is to resolve inflammation, making them overall the ‘good’ guys of the inflammatory process.

References:

  1. Yoshimura, T., Matsushima, K., Tanaka, S., Robinson, E.A., Appella, E., Oppenheim, J.J. and Leonard, E.J. (1987) Proc. Natl. Acad. Sci. USA 84, 9233-9237
  2. Campanelli, D., Detmers, P.A., Nathan, C.F. and Gabay (1990) J. Clin. Invest. 85, 904-915
  3. Albrich, J.M. and Hurst, J.K (1982) FEBS Lett. 144, 157-161
  4. Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D.S., Weinrauch, Y. and Zychlinsky, A. (2004) Science 303, 1532-1535
  5. Beiter, K., Wartha, F., Albiger, B., Normark, S., Zychlinsky, A. and Henriques-Normark, B. (2006) Curr. Biol. 16, 401-407
  6. Kerr, J.F., Wyllie, A.H. and Currie, A.R. (1972) Br. J. Cancer 26, 239-257
  7. Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L. and Henson, P.M. (1992) J. Immunol. 148, 2207-2216
  8. Colamussi, M.L., White, M.R., Crouch, E. and Hartshorn, K.L. (1999) Blood 93, 2395-2403
  9. Usher, L.R., Lawson, R.A., Geary, I., Taylor, C.J., Bingle, C.D., Taylor, G.W. and Whyte, M.K.B. (2002) J. Immunol. 168, 1861-1868
  10. Ottonelo, L., Cutolo, M., Frumento, G., Arduino, N., Bertolotto, M., Mancini, M., Sottofattori, E. and Dallegri, F. (2002) Rheumatol. 41, 1249-1260