What do neutrophils attack

It is not clear how tumors can induce neutrophilia, but a common mechanism seems to be the production by tumors of cytokines that influence granulopoiesis, including G-CSF McGary et al.

The presence of elevated numbers of neutrophils in the circulation is associated with poor outcome in several types of cancers Schmidt et al. In addition, the presence of neutrophils in tumors also seems to be an indicator of poor outcome Sionov et al.

For this reason, the counts of neutrophils in blood in relation to other leukocytes have been suggested as a prognostic value in cancer. Therefore, the neutrophil to lymphocyte ratio NLR was introduced as a simple and inexpensive biomarker for many types of cancer Peng et al.

In general, the blood NLR is high in patients with more advanced or aggressive cancers Guthrie et al. Despite the simplicity for using the NLR, it has not been accepted in many clinical settings. One reason for this is that neutrophilia can be the result of elevated granulopoiesis and as a consequence, it is not always a bad sign for cancer progression.

Another reason is that neutrophilia does not correlate with poor clinical outcome in all types of cancer. In gastric cancer, for example a high NLR is indicative of positive prognosis Caruso et al. This is indicative of the great plasticity neutrophils have. They can directly kill tumor cells and control cancer Yan et al. Therefore, the exact role of neutrophils within the tumor is a controversial matter Sionov et al. In several types of cancer, not only an increase in the number of neutrophils in blood is observed, but also an increase in immature myeloid cells Brandau et al.

These immature cells are at various stages of differentiation, accumulate in the spleen of tumor-bearing animals, and present an immunosuppressive phenotype that supports tumor progression Nagaraj et al. Hence, some researchers considerer them to be a bona fide phenotype of neutrophils Pillay et al. However, the relationship among these cells is not clear since immature neutrophils do not have immunosuppressive properties Solito et al. Neutrophil subsets that can be separated through density gradient centrifugation.

The bulk of mature normal neutrophils PMN are denser and separate at the bottom of the density gradient. These cells, named high-density neutrophils present the classical neutrophil morphology with a lobulated nucleus and many granules. In the upper part of the gradient, the less dense peripheral blood mononuclear cells PBMC are separated.

Among these cells, low-density neutrophils can be found. They comprise immature and mature neutrophils with immunosuppressive properties.

In humans the problem is more complex, since the Ly6G antigen does not exist. MDSC share all these markers, making it impossible to differentiate these cells from mature neutrophils. At present, it is not possible to distinguish whether MDSC are indeed subpopulations of neutrophils or a separate cell type Solito et al. An interesting subpopulation of neutrophils is the so-called low-density neutrophils LDNs. In contrast, LDNs are found in the low-density fraction Sagiv et al. Interestingly, the proportion of LDNs in the low-density fraction increases with tumor growth and progression Mishalian et al.

These LDNs are a subpopulation of neutrophils with characteristics and functions not well described. Although, LDNs were first reported in the blood of patients with SLE, rheumatoid arthritis, or rheumatic fever Hacbarth and Kajdacsy-Balla, , they attracted attention only recently because they seem to be associated with cancer Brandau et al. These LDNs have been found in many other pathological conditions including sepsis Morisaki et al. In addition, LDNs have been reported in natural pregnancy Ssemaganda et al.

During pregnancy, downregulation of T cell functions is required to ensure materno-fetal tolerance. Arginase activity is significantly increased in the peripheral blood of pregnant women and also in term placentae Kropf et al. This phenotype is suggestive of a activated neutrophil Fortunati et al.

Thus, situations of chronic inflammation and immunosuppression appear to induce neutrophil diversity. Very little is known about the function of these subpopulations of neutrophils.

These NETs could then assist the clustering and growth of free tumor cells disseminated in the abdomen. The origin of LDNs remains unclear. Since LDNs are a mixture of cells with segmented or banded nuclei and myelocyte-like cells, one thought is that LDNs are immature neutrophils that are released from the bone marrow during chronic inflammation or immunosuppression Denny et al. Another possibility is that these LDNs are activated neutrophils that have undergone degranulation and therefore they have a reduced density Rocha et al.

In mouse models of cancer, these LDNs seem to derive either from immature cells released by the bone marrow Youn et al. It is important to notice that these LDNs are still not properly characterized. The immunosuppressive function of these cells has not been directly determined and the transition of mature normal density to LDNs appears to involve an increase in volume rather than degranulation Sagiv et al.

Thus, most likely these LDNs are not activated normal neutrophils. In addition, since SLE patients have chronic inflammation, it is unlikely that their LDNs present immunosuppressive activity.

All these possibilities need to be further studied in the future. However, one serious limitation for the characterization of these cells is that there are not specific molecular markers that could distinguish among these possible neutrophils subpopulations.

The phenotypic changes of circulating neutrophils during tumor progression are also related to infiltration of neutrophils into tumors. Neutrophils in the circulation display different phenotypes. Mature normal neutrophils PMN leave the bone marrow and display the classical pro-inflammatory and anti-tumor properties of these cells. It is thought that these PMN can migrate into tumors and display an anti-tumor N1 phenotype.

In tumor-bearing mice, immature neutrophils, such as band cells, also leave the bone marrow into the circulation. These cells can infiltrate tumors and display pro-tumor N2 phenotype. The exact origin of recruited neutrophils is not known. Also, it is not clear if N1 cells can change into N2 cells and vice versa under the influence of the tumor microenvironment. Depending on the phenotype displayed by TANs in tumor-bearing mice, they have been classified as N1 or N2 Fridlender et al.

This classification is analogous to antitumor tumor-infiltrating macrophages M1 or protumor macrophages M2 Galdiero et al. Murine N1 TANs are proinflammatory and antitumorigenic. This means that TANs can display an antitumor N1 phenotype or a pro-tumor N2 phenotype depending on the tumor microenvironment Sionov et al.

In addition, in tumor-bearing animals the LDNs increased progressively in circulation, were not cytotoxic, and had reduced expression of cytokines Sagiv et al. This is consistent with the idea that some of the LDNs are indeed immature neutrophils Sagiv et al. It is important to emphasize here that the paradigm of N1 and N2 TANs has been described only in murine models of cancer, and that the nature and function of TANs in the tumor microenvironment remains largely unknown, particularly with human tumors.

There are only two reports on isolation of human TANs, but they describe controversial data on their immunosuppression capacity. In one report, TANs were isolated from digested human lung tumors Eruslanov et al. In another report, TANs were isolated from a colorectal tumor and found to present a typical neutrophil morphology.

Latter, the cells acquire an N2 phenotype and become immunosuppressive Wu et al. Recently, another important role of neutrophils in anticancer therapy has been described. Immunogenic cell death can stimulate neutrophils to utilize cytotoxicity against residual live cancer cells after therapy.

The concept of immunosurveillance explains how only the most immunoevasive or highly mutagenic neoplastic cells are able to generate clinically relevant tumors Dunn et al. Yet, the immune system is capable of recognizing altered-self molecules in damaged cells through endogenously derived danger signals or alarmins Bianchi, ; Garg et al.

Anti-cancer therapy-induced cancer cell death can be subdivided into three distinct types i. The details of these types of cell death are beyond the scope of the present publication, but the reader is directed to some excellent recent reviews Green et al.

Through immunogenic cell death, after some types of anti-cancer therapy Galluzzi et al. These signals trigger neutrophil phagocytosis of cancer cells and pro-inflammatory stimulation, leading to a change in neutrophil phenotype Garg et al.

As a result, neutrophils stimulated by immunogenic cell death showed cytotoxicity against residual live cancer cells Garg et al.

Thus, neutrophils interacting with immunogenic apoptotic cells gain a pro-inflammatory profile, culminating into neutrophil dependent cytotoxicity against residual cancer cells. The realization that neutrophils do in fact perform many more functions than just antimicrobial responses, and the fact that neutrophils with different phenotypes have been reported in various tissues and pathological conditions, suggest that indeed different neutrophils exist.

However, in most reports the evidence is circumstantial and we are in need for solid experimental proof that the cells described are in fact novel neutrophil subsets. What we have learned for sure so far is that in various pathological conditions, particularly cancer, distinct populations of mature and immature neutrophils are found in circulation. However, we have to highlight that the actual cell type responsible for the immunosuppressive properties of MDSC remains a mystery.

Many questions remain open, but at least two topics seem to be relevant at the moment. One important topic that needs to be addressed is whether mature neutrophils in circulation can be reprogrammed by external stimuli, or whether defined phenotypes are programmed in the bone marrow and neutrophils exit with a particular phenotypic signature. Evidence suggests that neutrophils are very plastic cells and in consequence the various subtypes described seem to be acquired in the tissues.

However, these possibilities need to be formally tested. Another relevant topic is that the many functions described have not been assigned to particular phenotypes of neutrophils. This remains a complex issue, as there are currently no appropriate molecular markers to readily identify these different neutrophil subpopulations. This confusing scenario is the fuel for new and even more exciting research. We expect to learn new tricks from our favorite cell type in the near future. The author confirms being the sole contributor of this work and approved it for publication.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Eileen Uribe-Querol for preparing the figures. National Center for Biotechnology Information , U. Journal List Front Physiol v. Front Physiol. Published online Feb Author information Article notes Copyright and License information Disclaimer.

Reviewed by: Abhishek D. This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology. Received Nov 2; Accepted Feb 5. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defense in the innate arm of the immune system. Keywords: neutrophil, bacteria, infection, inflammation, cancer.

Introduction Neutrophils, also known as polymorphonuclear PMN leukocytes, are the most abundant cell type in human blood. Open in a separate window. Figure 1. Figure 2. Neutrophil exit from the bone marrow Once neutrophils mature they can leave the bone marrow into circulation.

Neutrophil trafficking and clearance Neutrophils from the blood can be mobilized to sites of infection or inflammation through the process known as the leukocyte adhesion cascade Ley et al.

Neutrophil subpopulations in health The previous description of the neutrophil life cycle gives the idea that these cells are produced in the bone marrow, go to the circulation, migrate to sites of infection or inflammation, execute their antimicrobial functions, and then quietly are cleared by tissue-resident macrophages. Neutrophil subpopulations in the circulation In normal conditions, neutrophils remain in circulation for just few hours the half-life is estimated at 6—12 h before they leave into tissues Summers et al.

Figure 3. Neutrophil subpopulations in tissues In normal homeostasis, neutrophils are found in many tissues von Vietinghoff and Ley, , , where they perform specialized functions. Migrating neutrophil subpopulations Some neutrophils have been observed to perform reverse transendothelial migration rTEM or reverse interstitial migration rIM , depending on their initial location Nourshargh et al.

Neutrophil subpopulations induced by the microbiota Neutrophils can modify their functional responses after being exposed to multiple factors, through the process named neutrophil priming Downey et al. Neutrophil subpopulations in disease As discussed earlier, it is becoming increasingly apparent that neutrophils are much more than just microbe-killing cells. Neutrophil subpopulations in inflammation Neutrophils are the first cell type recruited to sites of inflammation. Neutrophil subpopulations induced by metabolic deregulation As mentioned before, neutrophil effector functions are markedly enhanced after priming.

Neutrophil subpopulations in cancer The changes in neutrophil phenotype during cancer are perhaps the most impressive and best studied so far. Myeloid-derived suppressor cells MDSC In several types of cancer, not only an increase in the number of neutrophils in blood is observed, but also an increase in immature myeloid cells Brandau et al.

Figure 4. Tumor-associated neutrophils TANs The phenotypic changes of circulating neutrophils during tumor progression are also related to infiltration of neutrophils into tumors. Figure 5. Immunogenic cell death Recently, another important role of neutrophils in anticancer therapy has been described. Author contributions The author confirms being the sole contributor of this work and approved it for publication. Conflict of interest statement The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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