Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious

Abstract

Sepsis, an overwhelming inflammatory response syndrome secondary to infection, is one of the costliest and deadliest medical conditions worldwide. Neutrophils are classically considered to be essential players in the host defense against invading pathogens. However, several investigations have shown that impairment of neutrophil migration to the site of infection, also referred to as neutrophil paralysis, occurs during severe sepsis, resulting in an inability of the host to contain and eliminate the infection. On the other hand, the neutrophil antibacterial arsenal contributes to tissue damage and the development of organ dysfunction during sepsis. In this review, we provide an overview of the main events in which neutrophils play a beneficial or deleterious role in the outcome of sepsis.

Keywords: chemotactic receptors; neutrophil migration; organ dysfunction; sepsis; toll-like receptors.

Figure 1

Neutrophil migration in sepsis. During non-severe sepsis, neutrophils expressing CXCR2 are recruited from the blood to the site of infection in response to CXCL2 and other chemoattractants. Neutrophils migrate to the locale of the infection, where they release NETs and produce reactive oxygen and nitrogen intermediates (such as NO) to kill the pathogens and avoid its spreading. By contrast, neutrophils are systemically stimulated during severe sepsis, which leads to impaired neutrophil migration to the infection focus. Bacterial components present in the blood activate TLRs expressed on neutrophils, leading to the up-regulation of GRK2, which induces desensitization of CXCR2 on the neutrophil surface. Additionally, TLR activation induces the expression of TNF-α and iNOS, the latter of which might also be activated by PI3K. Both TNF-α and NO can lead to upregulation of GRK2, exacerbating the down-regulation of CXCR2 on the neutrophil surface. As a consequence, neutrophil migration fails, and bacterial growth is not controlled. Furthermore, activation of TLRs also induces the expression of CCR2 on the surface of neutrophils, favoring the recruitment of these cells to distant organs producing CCL2, which contributes to organ damage in association with the capillary occlusion and the hypoperfusion observed in sepsis. The systemic activation of neutrophils also induces the release of NETs in the blood vessels, which causes endothelial damage, culminating in the aggravation of sepsis and possible death. Interestingly, it has been demonstrated that IL-33 can prevent the upregulation of GRK2 expression induced by TLR overactivation and consequently prevent the failure of neutrophil migration to the site of infection.