Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Neutrophil recruitment and function in health and inflammation

Scientists who study neutrophils often have backgrounds in cell biology, biochemistry, haematology, rheumatology or infectious disease. Paradoxically, immunologists seem to have a harder time incorporating these host-defence cells into the framework of their discipline. The recent literature discussed here indicates that it is appropriate for immunologists to take as much interest in neutrophils as in their lymphohaematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich our concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.

Neutrophils and immunity: challenges and opportunities.

Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: “N1” versus “N2” TAN

Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

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Neutrophils in the activation and regulation of innate and adaptive immunity

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Three Different Neutrophil Subsets Exhibited in Mice with Different Susceptibilities to Infection by Methicillin-Resistant Staphylococcus aureus

Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.

Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats.

Objective To determine the relationship between systemic inflammatory response syndrome (SIRS) and host innate immunities against bacterial infections. Design Controlled animal study. Setting University research laboratory. Subjects Male BALB/c mice, 8-10 wks of age. Interventions Morbidity and mortality rates of severe SIRS mice were compared with those of mild SIRS mice after infection with Enterococcus faecalis or methicillin-resistant Staphylococcus aureus (MRSA) or exposure to infectious complications induced by cecal ligation and puncture (CLP). In addition, a function of effector cells related to antibacterial innate immunities for these infections was analyzed in these two groups. Furthermore, SCIDbgMN mice (SCIDbg mice depleted of antibacterial effector cells) were reconstituted with effector cells from mild or severe SIRS mice and exposed to various infections. Measurements and main results Severe SIRS mice were greatly susceptible to E. faecalis, MRSA, and CLP-induced sepsis. On the other hand, as compared with normal mice, mild SIRS mice were resistant to these infections. All of SCIDbgMN mice inoculated with peritoneal macrophages (PMphi) from severe SIRS mice died after infection with E. faecalis or MRSA, whereas all SCIDbgMN mice inoculated with PMphi from mild SIRS mice survived after the same infection. SCIDbgMN mice that were inoculated with PMphi from normal mice and exposed to E. faecalis, MRSA, or CLP survived at rates of 50%, 50%, or 60%, respectively. PMphi from mild SIRS mice exhibited typical properties for classically activated macrophages (CAMphi), whereas those from severe SIRS mice exhibited typical properties for alternatively activated macrophages (AAMphi). Conclusions Mphi-associated host antibacterial innate immunities are greatly influenced by SIRS levels. CAMphi, effector cells for the antibacterial innate immunity against E. faecalis, MRSA, and CLP-induced sepsis, are induced in mild SIRS mice. AAMphi with no antibacterial capabilities are generated in mice with severe SIRS. Induction of CAMphi may protect severe SIRS patients against infections.

Influence of systemic inflammatory response syndrome on host resistance against bacterial infections.

Bacterial sepsis causes a high mortality rate when it occurs in patients with compromised host defenses Severely burned patients, typical immunocompromised hosts, are extremely susceptible to infections from various pathogens, and a local wound infection frequently escalates into sepsis In these patients, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa are familiar pathogens that cause opportunistic infections Also, polymicrobial sepsis frequently occurs in these patients In this review, therefore, the roles of chemokines in thermally injured patients infected with these 3 pathogens and polymicrobial sepsis will be discussed These infections in thermally injured patients may be controlled immunologically, because immunocompetent hosts are resistant to infections with these pathogens Classically activated macrophages (M1Mphi) are major effector cells for host innate immune responses against these infections However, M1Mphi are not generated in thermally injured patients whose alternatively activated macrophages (M2Mphi) predominate M2Mphi appear in patients early after severe burn injuries M2Mphi inhibit M1Mphi generation through the secretion of CCL17 and IL-10 As a modulator of Mphi, two different subsets of neutrophils (PMN-I, PMN-II) are described PMN-I direct the polarization of resident Mphi into M1Mphi through the production of CCL3 M2Mphi are induced from resident Mphi by CCL2 released from PMN-II Therefore, as an inhibitor of CCL2, glycyrrhizin protects individuals infected with S aureus Sepsis stemming from P aeruginosa wound infection is also influenced by CCL2 released from immature myeloid cells A large number of immature myeloid cells appear in association with burn injuries Host resistance to S aureus, E faecalis, P aeruginosa or polymicrobial infections may be improved in thermally injured patients through the induction of M1Mphi, elimination of CCL2 and/or depletion of M2Mphi induced by CCL2

Bacterial sepsis and chemokines.

Functional disorders of various immune cells have been reported in hepatocellular carcinoma (HCC) patients. Recently, distinct subsets of neutrophils (polymorphonuclear leukocytes, PMN) have been identified in hosts with enhanced or impaired cell-mediated immunity. In this study, therefore, plasma factors and PMN from HCC patients were immunobiologically investigated. Plasma neopterin and CCL17 levels were measured by ELISA in 95 HCC patients. Peripheral PMN were isolated from each HCC patient and tested for CCL2 or CCL3 production by ELISA and flow cytometry. The results showed elevated plasma neopterin levels in HCC patients, while CCL17 levels decreased in correlation with tumor size. PMN from HCC patients produced CCL2, while PMN from healthy subjects did not. Moreover, CCL2 production by PMN was significantly increased in proportion to tumor load. When HCC patients were divided into two groups based on CCL2 produced by PMN, the survival rate of the CCL2 high group was significantly lower than that for other patients. While CCL3 production by PMN was also significantly increased in HCC patients, their CCL3 production did not correlate with tumor load and survival. The CCL2/CCL3 ratio in culture fluids of each PMN was also increased in proportion to tumor size. These results suggest that cell-mediated immunity may be impaired in advanced HCC patients. Moreover, distinct PMN subsets may exist in the peripheral blood of HCC patients. These PMN subsets, especially CCL2-producing PMN, may be involved in tumor extension and the survival outcomes for HCC patients.

Yasuhiro Tsuda

Papers

Three Different Neutrophil Subsets Exhibited in Mice with Different Susceptibilities to Infection by Methicillin-Resistant Staphylococcus aureus

Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats.

Influence of systemic inflammatory response syndrome on host resistance against bacterial infections.

Bacterial sepsis and chemokines.

An immunosuppressive subtype of neutrophils identified in patients with hepatocellular carcinoma