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.

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Background Although literature demonstrates that an increase in both the number and suppressive function of CD4+FOXP3+T regulatory cells (Tregs) during sepsis contributes to an immunosuppressed state, little is known about the identity of these cells. Methods Using the sepsis mouse model of cecal ligation and puncture (CLP), we analysed the frequency and molecular signature of the TIGIT + and TIGIT- Tregs subsets by flow cytometry and qPCR. Additionally, ST2-/- and STAT6-/- mice were submitted to CLP or rIL-33 treatment to investigate the mechanism through which TIGIT+Tregs differentiate during sepsis. Results Sepsis was marked by the sustained expansion of the highly suppressive TIGIT +Tregs subset, which expresses Helios, Neuropilin-1, and high levels of Tnfrsf18 and Pdcd1 at 15d after CLP. The increase of the TIGIT +Tregs was accompanied by higher susceptibility to nosocomial bacteria challenge, suggesting its involvement with post-sepsis immunosuppression. Mechanistically, we found that the ST2 deletion abrogated the expansion of the TIGIT+Treg subset during sepsis. Furthermore, the treatment with rIL-33 resulted in the expansion of TIGIT+Tregs depending on the STAT6 and M2 macrophages. Conclusions These findings demonstrated that only the TIGIT+Tregs remain stably expanded at the late phase of sepsis. Moreover, the expansion of TIGIT +Tregs is dependent on the IL-33/ST2/STAT6/M2 macrophages axis.

Objective This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis. Methods Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wildtype (WT) mice and mice deficient in the gene Nfat1 (Nfat1 −/− ) in the C57BL/6 background. Animals were treated with 2.0 mg/kg of FK506, subcutaneously, 1 h before the sepsis model, twice a day (12 h/12 h). The number of bacteria colony forming units (CFU) was manually counted. The number of neutrophils in the lungs was estimated by the myeloperoxidase (MPO) assay. The expression of CXCR2 in neutrophils was determined using flow cytometry analysis. The expression of inflammatory cytokines in macrophage was determined using ELISA. The direct effect of FK506 on CXCR2 internalization was evaluated using HEK-293T cells after CXCL2 stimulation by the BRET method. Results FK506 treatment potentiated the failure of neutrophil migration into the peritoneal cavity, resulting in bacteremia and an exacerbated systemic inflammatory response, which led to higher organ damage and mortality rates. Failed neutrophil migration was associated with elevated CXCL2 chemokine plasma levels and lower expression of the CXCR2 receptor on circulating neutrophils compared with non-treated CLP-induced septic mice. FK506 did not directly affect CXCL2-induced CXCR2 internalization by transfected HEK-293 cells or mice neutrophils, despite increasing CXCL2 release by LPS-treated macrophages. Finally, the CLP-induced response of Nfat1 −/− mice was similar to those observed in the Nfat1 +/+ genotype, suggesting that the FK506 effect is not dependent on the NFAT1 pathway. Conclusion Our data indicate that the increased susceptibility to infection of FK506-treated mice is associated with failed neutrophil migration due to the reduced membrane availability of CXCR2 receptors in response to exacerbated levels of circulating CXCL2.