Specific depletion reveals a novel role for neutrophil‐mediated protection in the liver during Listeria monocytogenes infection

Abstract

Summary Previous studies have suggested that neutrophils are required for resistance during infection with multiple pathogenic microorganisms. However, the depleting antibody used in those studies binds to both Ly6G and Ly6C (anti-Gr-1; clone RB6-8C5). This antibody has been shown to not only deplete neutrophils, but also monocytes, and a subset of CD8 T cells. Recently, an antibody against Ly6G has been characterized which specifically depletes neutrophils. In the present study, neutrophils are depleted using the antibody against Ly6G during infection with the intracellular bacterium, Listeria monocytogenes (LM). Our data show that neutrophil depleted mice are much less susceptible to infection than mice depleted with anti-Gr-1. Although neutrophils are required for clearance of LM, their importance is more pronounced in the liver and during a high-dose bacterial challenge. Furthermore, we demonstrate that protection mediated by neutrophils is due to production of TNF-α, but not IFN-γ. Additionally, neutrophils are not required for the recruitment of monocytes or the generation of adaptive T cell responses during LM infection. These studies highlight the importance of neutrophils during LM infection, and also indicate that depletion of neutrophils is less detrimental to the host than depletion of all Gr-1 expressing cell populations.

Revisiting the protective and pathogenic roles of neutrophils: Ly‐6G is key!

“…Instead, TNF-a secreted from by neutrophils seems to help in killing LM-infected hepatocytes. These results of Carr et al [13] go against previous conclusions drawn regarding the roles of neutrophils in LM infection observed on the basis of anti-Gr-1 mAb-mediated depletion experiments, and reveal a precise role for neutrophils in controlling LM infection in the spleen and liver. Interestingly, Wojtasiak et al have shown in mice that specific depletion of Ly-6G 1 neutrophils does not modulate disease or alter virus replication following intranasal infection with HSV-1, whereas treatment of HSV-1-infected mice with the anti-Gr-1 mAb (clone RB6-8C5) leads to exacerbated virus replication and disease severity and increased mortality [14].…”

“…Altogether these recently published reports [13][14][15] highlight the importance of the Ly6G mAb (clone 1A8) for investigating the functions of neutrophils. Furthermore, the findings [13][14][15] remind us that all previous studies that used the anti-Gr-1 mAb (clone RB6-8C5) to investigate the roles of neutrophils need to be revisited and their conclusions reconsidered.…”

“…A report by Carr et al [13] in this issue of the European Journal of Immunology uses the Ly6G mAb (clone 1A8) to re-investigate several reported functions of neutrophils during LM infection; the report also demonstrates new roles for neutrophils during intracellular LM infection.…”

“…Furthermore, the findings [13][14][15] remind us that all previous studies that used the anti-Gr-1 mAb (clone RB6-8C5) to investigate the roles of neutrophils need to be revisited and their conclusions reconsidered. Neutrophils have been implicated in the pathogenesis of many kinds of diseases, with both inflammation-initiating (harmful) [3,16,17] and antiinflammatory (protective) [4,5] functions being reported; however, the mechanisms that modulate this plasticity of neutrophils remain unclear.…”

The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

“…However, activated macrophages display increased resistance to infection by L. monocytogenes (14). Neutrophils have been shown to play an important role in the control of L. monocytogenes infection in vivo (15,16). In vitro, human neutrophils kill a large portion of L. monocytogenes via both oxidative-dependent and -independent processes (17)(18)(19)(20)(21).…”