All You Ever Wanted To Know About Neutrophils

I once made a case that macrophages are the coolest cell ever. I stand by that – but neutrophils are pretty cool too. Here are ten reasons why.

  1. Neutrophils are an integral part of the innate immune system. They represent the first line of defense against invading pathogens. Up to 40% of our white blood cells are neutrophils. We produce about 1 × 1010 neutrophils per day (!) in the bone marrow.
  1. Neutrophils produce antimicrobial and immune mediators, store them in granules within the cells and then release them in large quantities when needed. This process is called degranulation. It kills intruders and further activates the immune system. In addition to degranulation, neutrophils are phagocytes – meaning they can engulf or “eat” the invaders. This feature makes any cell cool – remember: this binge eating is what I love about macrophages too!
  1. Neutrophils have one more (and let’s face it: even more extravagant!) way of clearing pathogens. If “provoked”, they explode and expel NETs (Neutrophil extracellular traps). The process is called Suicidal NETosis.  NETs are webs that consist of DNA and DNA binding/antimicrobial proteins, which can trap and kill microbes. These NETs can be big – just look at the title picture. They function as physical barriers that hinders pathogen spread and concentrates antimicrobial proteins.  
  1. Phagocytosis and degranulation can not coexist with suicidal NETosis, as the former requires the cells to be alive and the latter requires them to die. Sure, the cells could first eat and degranulate, and then expel NETs and die. Or they become zombies. Reports have shown that neutrophils can survive NETosis. But with their DNA expelled, via exocytosis rather than lysis of the cell membrane, there is a debate as to whether these neutrophils are still cells. What is for sure, is that these anurclear cells can still find and eat pathogens, no DNA needed. 
  1. Not all DNA found in NETs is nuclear. Reports have suggested that cells can expel mitochondrial DNA to form NETs. This is interesting, as it would allow the cell to stay alive (and retain their nucleus and nuclear DNA).
  1. Neutrophils stem from the bone marrow, and are produced in a continuous process called granulopoiesis. During an infection granulopoiesis can be accelerated. More neutrophils mature from stem cells and exit into the bloodstream to help fight the infection. Interestingly, mature neutrophils themselves can help initiate emergency granulopoiesis. Expelling reactive oxygen species (ROS) directly activates stem cell proliferation. In addition, TNFalpha produced by neutrophils after a bone marrow transplant helps restore the local cellular environment and helps the transplanted stem cells to engraft. 
  1. Neutrophils do not just help with granulopoiesis during an infection. Early primitive neutrophils produce TNFalpha and thereby (via Notch and NFkB signalling) initiate or establish the hematopoietic stem cell fate in cells of the embryo
  1. Like with all immune responses balance is important. Over-activation of neutrophils and NETs can be counterproductive, when the cells amplify further immune activation and expel toxic antimicrobial substances injuring the surrounding tissue. A kind of collateral damage.  For example, in Covid-19 cases, increased neutrophil numbers (neutrophilia) has been linked to tissue damage in the lung and higher mortality.  Tissue damage can also occure when neutrophils are recruited during sterile inflammation. A process when the immune system is activated even though no pathogen is invading the body. Processes like injury, trauma, cancer and autoimmunity have been reported to involve neutrophil associated tissue damage.
  1. To make things more complicated, neutrophils cannot just cause damage but also play a role in the subsequent tissue repair. Phagocytosing (“eating”) debri, they clean the injured tissue. Neutrophils further produce and expel messenger molecules aiding cellular growth and angiogenesis – the making of new blood vessels. Finally, neutrophils aid regeneration by suicide, again. Becoming apoptotic, neutrophils help shut down the local immune response. But do not worry not all die – some enter circulation again.
  1. Neutrophils are a hallmark of RSV (and other airway) infections. A new study suggests that their presence in healthy lungs can predicted if we are prone to getting colds. Infecting volunteers (adults, for which the virus only causes cold symptoms), 57% of them developed symptoms. While the people who remained healthy mounted a quick IL-17 based immune response clearing the virus, people destined to become sick showed neutrophils in their lungs prior to infection. They subsequently did not mount a protective IL-17 response, but a pro-inflammatory response that did not clear the virus. This suggested that the immune environment in the lung can be the deciding factor on whether we get sick or not. Whether we are prone to colds or stay healthy all winter.  

Picture credit: Carmelo Carmona-Rivera, Ph.D., NIAMS Systemic Autoimmunity Branch, Mariana J. Kaplan, M.D., Chief. CC BY-NC-SA 2.0 Found on Flickr.