Neutrophils have historically been characterized as first responder cells vital to host survival due to their ability to contain and eliminate bacterial and fungal pathogens. However, recent studies have shown that neutrophils participate in both protective and detrimental responses to a diverse array of inflammatory and infectious diseases. Although the contribution of neutrophils to extracellular infections has been investigated for decades, their specific role during intracellular bacterial infections has only recently been appreciated. During infection with the gram-positive intracellular pathogen Listeria monocytogenes, neutrophils are recruited from the bone marrow to sites of infection where they utilize novel bacterial sensing pathways leading to phagocytosis and production of bactericidal factors. This review summarizes the requirement of neutrophils during Listeria monocytogenes infection by examining both neutrophil trafficking and function during primary and secondary infection.
Neutrophils and inflammatory monocytes are innate immune cells essential for protection during Listeria monocytogenes infection. Although certain functions have been generally assigned to each of the cells, similarities and differences in functions necessary for bacterial clearance have not previously been investigated. In the current study, phagocytosis, phagosomal containment, bacterial killing, and cytokine production by neutrophils and monocytes during L. monocytogenes infection were studied. Data obtained via in vitro studies show that neutrophils are more effective at L. monocytogenes uptake, phagosomal containment, and killing than monocytes. However, monocytes were found to be more effective at cytokine production during L. monocytogenes infection, in vivo. Additionally, the data demonstrated that neutrophils and monocytes are also capable of producing IL-1α, a cytokine that does not yet have a clearly defined role during infection with L. monocytogenes. Furthermore, we were able to demonstrate a population of monocytes producing both TNF-α and IL-α, concurrently. This study highlights the multifunctional capabilities of neutrophils and monocytes, further adding to our knowledge of these innate immune cells during L. monocytogenes infection.
Extracellular superoxide dismutase (ecSOD) is commonly regarded as having a protective function during ROS induced inflammation. However, using ecSOD congenic mice expressing differing levels of ecSOD activity (HI, WT & KO), we found that high ecSOD activity is not conducive to host survival during Listeria monocytogenes (Lm) infection. Interestingly, although the infected ecSOD HI mice had a higher percentage of neutrophils present in the target organs in comparison to the ecSOD KO mice, they also had a higher bacterial burden. To better understand the function of neutrophils during infection with Lm, we studied phagosomal containment in the context of varying levels of ecSOD activity. A higher percentage of KO neutrophils took up and allowed for phagosomal escape of Lm. However, although there was no difference in the relative amount of Lm that escaped per neutrophil in the context of ecSOD activity, the KO neutrophils took up more Lm than the HI neutrophils. Therefore, neutrophils from the KO mice were more effective at keeping Lm contained in comparison to the HI neutrophils. The effect of ecSOD on the ability of monocytes to contain Lm was also analyzed. It was observed that ecSOD had no effect on monocyte association and phagosomal containment of Lm. However, independent of ecSOD, a lower percentage of monocytes associate with and allow for phagosomal escape of Lm, in comparison to neutrophils. In conclusion neutrophils are more effective than monocytes at phagocytosis of Lm and ecSOD activity hinders neutrophil phagosomal containment of Lm. Future studies focused on how ecSOD activity modulates downstream neutrophil functions, such as Lm killing, will lead to a better understanding of the overall effects of ROS on neutrophil functions.
Extracellular superoxide dismutase (ecSOD) is an enzyme associated with the extracellular matrix that plays a protective role during reactive oxygen species mediated inflammatory responses. Previously, we reported that neutrophils are essential for protection during infection with Listeria monocytogenes (LM), and that high ecSOD activity is detrimental to host resistance during infection, while lack of ecSOD activity is beneficial. Furthermore, using depletion studies, it was determined that neutrophils from ecSOD KO mice are more protective than neutrophils from ecSOD expressing mice during LM infection. To understand how ecSOD modulates neutrophil function during LM infection, bacterial uptake and phagosomal escape were measured. A higher percentage of neutrophils from the spleen and liver of ecSOD KO mice associated with and allowed for phagosomal escape of LM. However, using MFI as an indicator of the relative number of bacteria per neutrophil, we observed that the ratio of cell associated to cytosolic bacteria was higher in ecSOD KO neutrophils in comparison to neutrophils with ecSOD activity. These data suggest that the absence of ecSOD activity enhances neutrophil association with LM and simultaneously limits LM escape from the phagosome. Future studies utilizing neutrophils obtained from other organs as well as from infected mice should help conclusively determine how the lack of ecSOD activity enhances the protective capabilities of neutrophils.
Neutrophils and monocytes have previously been shown to be important for host protection during infection with Listeria monocytogenes (Lm). Previous studies have shown that simultaneous depletion of neutrophils and monocytes with the Gr-1 antibody leads to susceptibility to Lm infection. The purpose of these studies is to delineate differences in function between neutrophils and monocytes during Lm infection. Neutrophils obtained from the bone marrow, liver and spleen of C57BL/6 mice were more effective at phagocytosis of Lm in comparison to monocytes as they had a higher total bacteria MFI than the monocytes. To determine differences in the ability of the cells to keep bacteria contained in the phagosome, the cells were infected with a strain of Lm that only expresses GFP when the bacteria escapes out of the phagosome into the cytosol. Comparison of the MFI of total bacteria present vs escaped bacteria showed that monocytes allowed for more bacteria to escape in comparison to neutrophils. Therefore, monocytes are less effective at bacterial containment in comparison to neutrophils. To ascertain differences in killing ability, bone marrow neutrophils and monocytes were sorted for a killing assay and neutrophils were also more effective than monocytes at bacterial killing. In conclusion, although both cell types are important for protection during Lm infection, neutrophils appear to be essential for protection as they are more effective at phagocytosis, phagosomal containment and bacteria killing. Future studies, such as measurement of ROS/RNS as well as cytokine production, will aid in further defining specific functional differences between neutrophils and monocytes during intracellular bacterial infection.
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