22 Responses

  1. Orezime Uyeh
    Orezime Uyeh at | | Reply

    This is the first time that I am hearing about the Wallerian degeneration, as well the other role neutrophils play in the body besides phagocytizing pathogens and creating neutrophil extracellular traps (NETs). However, I was curious to learn more about nerve cell regeneration and other cells and molecules that participate in the nerve regeneration, and some articles have discussed such molecules and cells. For example, IL-10 is a cytokine that plays an important role in inflammation and regeneration of nerve cells.  IL-10 is an anti-inflammatory cytokine, and in one study, it helps with resolving inflammation and promoting regeneration of a sciatic nerve crush injury in mice. According to the study, macrophages express IL-10 to control how many macrophages enter or leave the site of nerve injury. It also reduces the expression of chemokines and cytokines that promote inflammation. By lacking IL-10, axon regeneration is impaired. More specifically, without IL-10, macrophages cannot be induced to become anti-inflammatory and therefore, remain pro-inflammatory. Potential studies can research on how lacking chemokines (CXCL1 and CXCL2) could affect neutrophil recruitment or cellular debris clearance altogether. 
    Reference:  http://www.jneurosci.org/content/35/50/16431  

  2. Mallory Coody
    Mallory Coody at | | Reply

    In an article published by Acta Neuropathological the roles of macrophages in PNS injury and repair are studied. It was found that macrophages contribute to Wallerian degeneration but can also be polarized to an anti-inflammatory phenotype by the local microenvironment to contribute to axonal regeneration. Macrophages can be separated into the “classically activated” pro-inflammatory phenotype(M1) and “alternatively activated” antinflammatory phenotype (M2). M1 macrophages are activated by lipopolysaccharide (LPS), interferon gamma (IFN-γ) and/or tumor necrosis factor alpha (TNF- α). While M2 macrophages are activated by exposure to specific cytokines and factors, including IL-4, IL-13, IL-10, immune complexes, hormones or adenosine A2A receptors (A2AR) agonist. M1 macrophages will kill tumor cells and microorganisms by activating the immune responses. While M2 macrophages promote tissue remodeling and repair. While the neutrophils in the study were able to clean up the debris when lacking macrophage functionality, the study should expand to determine if the same tissue remodeling and repair functions are promoted in neutrophils.


  3. Raeesa
    Raeesa at | | Reply

    This study proposes that neutrophils are critical for debris clearance in peripheral nerve injuries. CCR2 -/- mice did not exhibit reduced injury clearance due to the neutrophil compensation. However, depletion of neutrophils resulted in debris clearance impairments suggesting that there is no alternant compensation for the loss of neutrophils. I felt that the study however, did not go into much depth with regards to their findings and Schwann cells. Schwann cells are supportive cells present in the peripheral nervous system that can both regenerate and support axon formation while also phagocytosing damaged myelin debris through a pathway that seems to be independent of both macrophages and neutrophils. They have been characterized as the first responders to a PNS injury and also the regulators of the inflammatory response, responsible for secreting chemokines that impact the inflammatory response. While the relationship between Schwann cells and macrophages is well characterized there does not seem to be much research on their relationship with neutrophils. It would be interesting to see if there is a direct connection between Schwann cells and neutrophils.

    1) Axon degeneration: Make the Schwann cell great again (https://www.ncbi.nlm.nih.gov/pubmed/28553320)
    2) Wallerian degeneration: Gaining perspective on inflammatory events after peripheral nerve injury (https://www.ncbi.nlm.nih.gov/pubmed/21878126)

    1. Sarah Leeann Smart
      Sarah Leeann Smart at | | Reply

      This is a very good point and an intelligent thought process on how to further this research. I would also like to see how Mast cells interact with neutrophils, because Mast cells have many functions, such as involvement in inflammatory responses, resistance to infection, and tissue repair/regeneration. Further research should be done how mast cells communicate with nerves and furthermore neutrophils, what cytokines are released upon mast cell activation, how these cytokines affect the cells involved during an immune response or injury.


  4. Kingsley Nwaobasi
    Kingsley Nwaobasi at | | Reply

    It was interesting to know that neutrophils are crucial for myelin removal in the cleanup of nerve debris when the receptors (CCR2) on the surface of macrophages are absent. However, a study done by Akashi et al in 2000 confirmed that phagocytes, including neutrophils and macrophages, originate from hematopoietic stem cells and differentiate through common pathways that also lead to immature myeloid DCs. Furthermore, macrophages and neutrophils share important features with respect to their common origin which includes; avid phagocytic capabilities as pointed out by Dale et al in 2008, the presence of common surface markers like chemokine receptors as shown by Silva in 2010, and common patterns of cytokine and chemokine secretion (Silva, 2010). Therefore, it will be fascinating and rewarding to understand if both macrophages and neutrophils could function simultaneously in cleaning the axonal and myelin debris damaged by neurodegenerative disease.

  5. Raven Gougis
    Raven Gougis at | | Reply

    Macrophages have been the key players in offering its phagocytic properties in clearing myelin and axon debris from nerve injuries and creating an environment for cellular regrowth to flourish. A study published on Oct.25, 2017 revealed that neutrophils actually play a vital role in this cellular clearance and regrowth mechanism. The study used a mouse model with a sciatic nerve injury. Results showed that chemokines cxcl1 and cxcl2 were elevated in the model; these are chemoattractants that are specific to the surface of neutrophils in helping cells move to the damaged tissue. Proving that neutrophils are actually the key plays in this process. With further research of this topic, I found a study published in the Journal of Biochemistry explaining that microglia and T lymphocytes were seen at the injury site early on and even in the late stages of sciatic nerve injuries. While other immune cells definitive to the start of an immune response such as macrophages and neutrophils, permeate the damaged nerves of spinal cord and brain injuries early on, these cells seem to be absent in the later stages. Although it is important to understand that neutrophils play a major role in cell debris clean up, there are other immune cells such as microglia and T lymphocytes that play a key role in the later stages to promote nerve regrowth as well.

  6. Justin
    Justin at | | Reply

    This article demonstrates the importance of neutrophils as well as macrophages in their role of repairing damaged nerves within the body. Neutrophils have been shown to be vital contributors in the removal of “cellular debris” and to help clean the damaged areas. The authors concluded that this information could be used as a form of therapy to relieve those of neurodegenerative diseases, such as, Alzheimer’s Disease. Another study also showed the role of neutrophils in AD formation but suggested using the neutrophil count as a type of marker to identify early stage Alzheimers. Gabriela Constantine and colleagues have shown that neutrophils are able to cross the blood brain barrier and migrate into the brain. Neutrophils were shown to congregate in areas of plaque formation that occurs in those suffering from AD. Areas of neutrophil formation not only helped locate plaque formation, but also helped reduce amyloid load and increase long term memory. The studies also reported high expression of adhesion factors within the brain suggesting that the brain was anticipating the capture of white blood cells found in circulation. Furthermore, the experimental addition of amyloid plaques in mice induced an increase in cell adhesion molecules found within the plaque formation. These adhesion molecules were shown to be the main contributors of the neutrophil formation found in close proximity to the plaque formation. However, this formation of neutrophils also causes devastating side effects like NETs and other toxic substance release. To test the negative effects of neutrophils on Alzheimers neutrophil congregation in the brain was blocked. In treated mice this blockage showed performance levels in the Y maze equal to that of the wild type mice as well showing a significant decrease in plaque formation within the following eight months. This data shows the importance of neutrophil activity in AD development. However, it was suggested that in order to have an effect on AD development and prevention early detection was essential due to the high inflammatory response that occurs in the early stages. Both studies support the idea that neutrophils may be used as a therapy as well as identification of AD.


  7. Philip S.
    Philip S. at | | Reply

    According to the author, injuries to peripheral nerves illicit an immune response. This response is known as the Wallerian degeneration and involves a degenerative process wherein macrophages come to the damaged site and clear away cellular detritus such as detached axons and myelin. Initially, it was believed that macrophages were central and that neutrophils were peripheral in this process. However, later research demonstrated that neutrophils were key components of the Wallerian degeneration and were capable of picking up the slack when macrophages were experimentally excluded. The attribute that is of significant interest is that the process of Wallerian degeneration gives rise to nerve cell regeneration.

    In light of this discovery, I looked up an entry in the Journal of Neuroinflammation on neutrophil involvement in spinal cord repair. This study, presented by Neirinckx Et Al., indicated that neutrophils have traditionally been viewed as detrimental with harmful effects. However, their research demonstrated that neutrophils can, in fact, contribute to cellular regeneration. For instance, neutrophils were found to induce inflammation-mediated remodeling of tissue in addition to releasing endothelial growth factor IL-8. Although the involvement of neutrophils in cellular regeneration appears promising, the authors did caution that our current understanding of neutrophil involvement in this process neophytic. Much work remains to be done in this field.

    The title of this cited paper is “Neutrophil contribution to spinal cord injury and repair”

    Please see the following link to the journal entry for additional information.


  8. Rouzbeh Teimouri
    Rouzbeh Teimouri at | | Reply

    It has been shown that neutrophils, in managing damaged tissue, travel to the area of damage in swarms; and in doing so, induce a separation of the wounded area, wherein all cells are forced to die, from the surrounding viable tissue, where later multiplication regenerates the wound. The article likened the behavior to the swarming of insects as it is highly organized with heavy reliance on communication [1,2].
    When it comes to nerve regeneration, there are multitudes of related diseases and disabilities that are in dire need of new therapeutics. There has already been an ongoing interest in mitigating the side effects of allotransplantation (the transfer of cells from a genetically non-identical donor), which includes a risk of lifelong induced immunosuppression in the receiver [3].
    The article above points to the nerve-regenerating ability of neutrophils as part of the groundwork for immunotherapeutic search into employing the body’s own cells in engineering therapeutic approaches. Although it seem far and away, the potential to re-engineer neutrophil swaming, and redirect it at the damaged nerves may be a plausible approach in increasing the effectiveness of any neutrophil involved therapeutic measures. Before any in-vitro work, however, the basic science must be well understood.

  9. Casey
    Casey at | | Reply

    Neutrophils are known as one of the first immune cells at the sight of infection that aid in the initial immune response responsible for inflammation. This blog post discusses the role of neutrophils as a mechanism for clean up of damaged nerve debris which makes sense because neutrophils have the capacity to phagocytize and remove harmful pathogens. However, neutrophils were not always seen in this positive light. A study published earlier this year actually depicted neutrophils as a player in the pathogenesis of diabetic neuropathy. It was found that there was an increase in L-selectin, which is vital for neutrophil migration across tissues, in spinal cord parenchyma as well as an increase in neutrophils in the parenchyma of the lumbar spine in diabetic mice. This was not seen in normal and diabetic mice treated with gabapentin, which is a common neuropathic preventative drug. With the increase in neutrophils, there also accompanied an increase in cytokines and other chemokines that were found to contribute to prolonged pain and sensitivity.
    I find this interesting as peripheral nerve disease is chronic and inflammatory, but after an initial injury whether from diabetes or trauma neutrophils are now seen more as the “clean up crew” that aids in recovery versus the reason for continued pain. Because treatment for neuropathy is long term this makes me question the benefit of neutrophils if it’s the problem or the cure. I have attached the article for reference!

  10. A. Ferrell
    A. Ferrell at | | Reply

    The blog post states that damage to nerve cells or peripheral nerves cause Wallerian degeneration which activates chemoattracts – Cxcl1 and Cxcl2 for neutrophil migration. The neutrophils enter the injured tissue and phagocytize cellular debris. However, macrophages are usually number one for cellular clean up. It makes you wonder why axons would prefer neutrophils when macrophages are known to perform similar tasks as neutrophils. In addition, macrophages are proximal in tissue, engulf larger particles, and has longevity (1). So, why would neutrophils be significant for nerve cell regeneration? Surprisingly, neutrophils disregard spontaneous apoptosis for up to 3 days during inflammation to clear up cellular debris. Further, neutrophil tertiary granules have an enzyme that if regulated has the potential to allow the formation of blood vessels and tissue regeneration (2).


    1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744134/
    2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274707/

  11. SauceTargaryen
    SauceTargaryen at | | Reply

    It’s quite interesting that neutrophils would be used in this process of cleaning up the nerve cells that have been damaged firstly because I was originally taught that a process like this didn’t take place but secondly always imagined the cells of the immune system being limited in some capacity. But for them to be able to clear debris in the peripheral nervous system is impressive. More than that the article I have linked below shows a study where they where able to manipulate the neutrophils of the CNS to regulate T cell responses. I wonder could that lead to the same thing happening in the CNS where it leads to some sort of immunoregulatory activity which could see cels of the immune system targeting damaged tissue to remove leaving it open to be repaird via surgery or otherwise.


  12. Zach M
    Zach M at | | Reply

    In this study, Dr. Zigmond and his team demonstrated the importance of macrophages in nerve regeneration. They proposed that macrophages act on axonal injury sites by clearing the cellular environment of debris after nerve damage occurs, allowing for the neuron to begin to regenerate. However, a recent study published by Sulaiman et al in the Journal of Neurosurgery suggests that dermal application of TGF-Beta to the site of a injured nerve can promote growth and regeneration. These two cutting edge findings appear to contradict each other by stating that macrophages are needed for neuronal repair, yet TGF-Beta, a cytokine that inhibits and suppresses macrophages also promotes neuronal regeneration. I think this contradiction illustrates that there is still a great deal of research that needs to be done to understand how the immune and nervous system interact before claims can be made suggesting that any single immune element is pivotal in nerve regeneration.



  13. Byron Lee
    Byron Lee at | | Reply

    The chemokines CXCL1 and CXCL2 attach to the surfaces of neutrophils and guide them to the site of nerve injury. In “Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases”, Kubben and Misteli state that CXCL1 and CXCL2 are partway responsible in chronic activation of the RB-p16 and p53-p21 pathways, which then result in clearing senescent cells by the immune system. I think that CXCL1 and CXL2 chemokines can guide engineered neurogenerative stem cells to sites of injury. After cleanup, ageing or injured nerve damage can be repaired with new pathways grown by “helper” stem cells with the proper chemokine receptors.

    Link: https://www.nature.com/nrm/journal/v18/n10/abs/nrm.2017.68.html

  14. Robert Taylor IV
    Robert Taylor IV at | | Reply

    Neutrophils are AMAZING! They are usually known for fighting infection by gathering at the site of the infection, and then they surround the antigen and consume them using lysosomes. Researchers in this study have discovered that they also help the nervous system clear debris, which facilitates nerve regeneration after injury. The researcher showed that neutrophils could clean up nerve debris. Previous research attributed nerve cell damage control to macrophages other cells. By identifying this role in the neutrophils of helping to facilitate debris removal after injury researchers can now use this to help repair additional nerve cell damage. How Neutrophils respond to nerve regeneration is a significant finding regarding finding ways to improve nerve regeneration of damaged or severed nerves.

  15. Anthony Kram
    Anthony Kram at | | Reply

    I enjoyed reading this article because it shed light for me as to the severity of peripheral nerve injuries, and their impact overall on the body. However, the more fascinating concept to me was that of Wallerian degeneration. Based upon the article provided, and another article I located, “The Neuroimmunology of Degeneration and Regeneration in the Peripheral Nervous System”, upon the the distal axonal segment degenerating, a process begins of regeneration with the cell body. Like the article, the paralleling article by DeFrancesco-Lisowitz outlines how the degeneration process occurs not only in the Peripheral Nervous System, but too the Central. However though, in the PNS, the influx of cells helps the body to rid itself of debris in an effort to begin the regeneration process, but in the CNS, it inhibits regeneration. Both experiments were carried out by way of mice, but what I would be interested in seeing if how would the results of Wallerian degeneration compare in terms of results if the experiment tested on human subjects that both had and did not have the CCR2 gene possibly affecting the macrophages functioning to see if the findings between mice and humans would be similar? Also, run the experiment on the central nervous system in human subjects to see if regeneration would still be inhibited, as is the case in mice?

    Citation: DeFrancesco-Lisowitz, A., Lindborg, J. A., Niemi, J. P., & Zigmond, R. E. (2015). The Neuroimmunology of Degeneration and Regeneration in the Peripheral Nervous System. Neuroscience, 302, 174–203. http://doi.org/10.1016/j.neuroscience.2014.09.027

  16. Seshata
    Seshata at | | Reply

    Even though there are several cells involved with cleaning up the remains left behind in damaged areas, from infection. Neutrophils, which we initially were viewed as having a more silent role, proved to be a more integral part in disposing remnants of nerve cells, than macrophages. Macrophages and neutrophils are both innate immune response cells. This post speaks specifically about peripheral nerve damage. This made me wonder if adaptive immune response cells (T or B cells) were involved in the nervous cell debris removal and how their involvement could tie into treatment for neurogenerative diseases. A study conducted, by a group of Stanford University School of Medicine’s neurobiologists, found that the absence of antibodies in the central nervous system is why nerve damage does not get repaired well in the brain and spiral cords. They also discovered that antibodies play a significant role in repair to the peripheral nervous system. Antibodies have little access to the central nervous system, while macrophages are present. Their hope is using by using antibodies, to clean up and promote regeneration in central nervous injuries, that lack the same pathways and mechanisms that peripheral nerve injuries do.


  17. Kelly Freeman
    Kelly Freeman at | | Reply

    Neutrophils play a major role in the immune system as being one of the first cells to aid in the initial response of inflammation. This article discusses how macrophages have been the cell type in the immune response to Wallerian degeneration. The macrophages were responsible for removing the cellular debris that is found after a nerve injury, but there is recent information that shows that neutrophils role in the removal of cellular debris is just as beneficial for the healing process. This shows that the loss of macrophages resulted in the neutrophils having a major role in the debris clean-up process when it came to the mutant mice. When the neutrophils were depleted, the debris was not cleared out the way that it was when the neutrophils were apart of the process. This truly shows that the neutrophils role is much more significant than once believed and even more so in comparison to the macrophages. Plus, it appears that the neutrophils pick up where the macrophages don’t quite get the job done. On one hand, the neutrophils seem to be more efficient when the macrophages are depleted. On another hand, I thought it was important to acknowledge the fact that neutrophils and macrophages also share dual roles especially when it comes to inflammation with tissue damage and repair. In an article by Butterfield et al., they reviewed the roles in which macrophages and neutrophils both respond at different times in order to repair injured tissue. Neutrophils and macrophages coexist at the site of injury but interact in different ways. The article that talked about this dual responsibility is below.


  18. Panda Southtown
    Panda Southtown at | | Reply

    I found it quite surprising that neutrophils were picking up so much of the slack from the macrophages to clear out the nerve debris! What a surprise!

    I wonder if unlocking the processes involved in neural injury repair and regeneration could possibly lead to new and/or better treatments for peripheral nerve injury, or neurodegenerative diseases like Guillain-Barre syndrome, Huntington’s Disease or Multiple Sclerosis.

    To further understand these mechanisms of neuro-inflammatory signals to regulate cell types, perhaps neutrophils and other cells could be examined specifically in the context of necessity or sufficiency experiments with respect to the SOCS1 and SOCS3 genes/proteins, as they suppress cytokine signaling, preventing the inflammation response from going on too long and becoming excessive.


  19. Owlette
    Owlette at | | Reply

    This is an interesting read and corresponds with the findings by Cashman and Hoke. These researchers found that Wallerian degeneration and subsequent debris clearing was unaffected in the presence of a deficient adaptive immunity. The major role that neutrophils play in debris clearing helps explain the finding of this research. This is because Neutrophils are a part of innate immunity, and therefore would be unaffected in the case of adaptive immunity deficiency.

    Source: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177070

  20. Nate
    Nate at | | Reply

    Peripheral nerves have the capability to repair stretched and damaged nerves. Contrasted with the CNS, it rarely has this extraordinary capability. Many cells and their functions play major roles in repairing and fixing these damaged areas in the PNS, such as neutrophils, macrophages, and Schwann cells. The main goal of the post was to show the active role that neutrophils play in the response to damaged nerves in the PNS. While this activity may be beneficial in one location, the damage could be amplified in another. One study found that using an optic nerve sample, neutrophils would secrete Oncomodulin (Ocm) which would participate in inflammation induced regeneration. While Ocm induced inflammation to increase regeneration, a different studied found that increased inflammation, due to increased expression galectin-3 molecules, had showed a decrease in regeneration. It would be interesting to see how both molecules would respond to the presence of each other, or if both molecules have receptors on neutrophils to play a role in stimulation or inhibition of neuronal regeneration. It would also be interesting to see if they have any affects against CCR2 receptors and/or regulation of Cxcl1 and Cxcl2 on the surface of neutrophils.
    Links to both papers have been provided for your perusal.


  21. Sarah Leeann Smart
    Sarah Leeann Smart at | | Reply

    It has been studied that neutrophils are a large part of the immune reaction, and the immune and nervous system work in tight conjunction to respond to injury and illness. Recent studies of peripheral nerves, and particularly the sciatic nerve, have shown that multiple players are involved when a nerve site is injured. Complement proteins C5a and C3a were shown to increase the sensitivity of C fiber nociceptors when applied ex-vivo, though receptors for these complements are present in these cells in vivo. These complements (more importantly C5a) in turn attract neutrophils and initiate the inflammatory response. I believe to further understand the interplay between neutrophils, the complement system, and pain, we need to further elucidate the effects of the complement cascade, specifically interactions with C5a. Understanding this would give us a better understanding of the neutrophil’s role, and the interactions between the immune system and nervous system.


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