Targeting neutrophils in sepsis

Abstract

Sepsis continues to have a high mortality rate worldwide. The multi-step effects of this syndrome make it difficult to develop a comprehensive understanding of its pathophysiology and to identify a direct treatment. Neutrophils play a major role in controlling infection. Interestingly, the recruitment of these cells to an infection site is markedly reduced in severe sepsis. The systemic activation of Toll-like receptors and high levels of TNF-α and nitric oxide are involved in the reduction of neutrophil recruitment due to down-regulation of CXCR2 in neutrophils. By contrast, CCR2 is expressed in neutrophils after sepsis induction and contributes to their recruitment to organs far from the infection site, which contributes to organ damage. This review provides an overview of the recent advances in the understanding of the role of neutrophils in sepsis, highlighting their potential as a therapeutic target.

Keywords::

• chemotaxis
• innate immunity
• neutrophil
• organ damage
• sepsis

Acknowledgement

The authors would like to express their gratitude to Caio Abner for his helpful contribution in drawing the figure.

Financial & competing interests disclosure

The authors have received financial support from European Union Seventh Framework Programme (FP7-2007-2013) under grant agreement number HEALTH-F4-2011-281608 (TIMER), from São Paulo Research Foundation (FAPESP) under grant agreements number 2011/19670-0 (projeto temático) and 2013/08216-2 (Center for Research in Inflammatory Disease), and from University of São Paulo NAP-DIN under grant agreement number 11.1.21625.01.0. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Sepsis still challenges researchers and clinicians worldwide due to the absence of effective direct treatments.

• Neutrophils are key players in the innate immune response, and their recruitment to infection sites is crucial to controlling bacterial/fungal growth.

• The chemotactic response of circulating neutrophils is impaired in septic patients and mice. Moreover, neutrophil migration to the infection site is markedly reduced in septic mice.

• Circulating neutrophils isolated from septic patients and mice exhibit diminished expression of CXCR2 via a process dependent on G protein-coupled receptor kinase 2 upregulation. Systemic activation of toll-like receptors, TNF-α and high levels of nitric oxide are involved.

• Although they are essential to controlling infection, neutrophils can be harmful and induce secondary organ damage during infection. Neutrophil recruitment to organs far from the infection site is facilitated by the expression of CCR2 under septic conditions.

• Impairment of neutrophil function has been reported in diabetic and immunosuppressed patients. Interestingly, these conditions have been implicated as sepsis comorbidities.

• Acute phase proteins released under sepsis conditions contribute to the impairment of neutrophil migration to the infection site.

• Neutrophils may be potential targets for treating sepsis.

Notes