Elsevier

Journal of Infection

Volume 77, Issue 5, November 2018, Pages 391-397
Journal of Infection

Galectin-3 aggravates experimental polymicrobial sepsis by impairing neutrophil recruitment to the infectious focus

https://doi.org/10.1016/j.jinf.2018.06.010Get rights and content

Abstract

Sepsis is an overwhelming systemic inflammation resulting from an uncontrolled infection that causes extensive tissue damage, organ dysfunction and eventually death. A growing body of evidence indicates that impaired neutrophil migration to the site of infection is associated with poor outcome in sepsis. Here we show that galectin-3 (Gal-3), an endogenous glycan-binding protein, plays a critical role in sepsis outcome. We found that serum Gal-3 concentration increased in patients with septic shock and mice undergoing sepsis induced by cecal ligation and puncture (CLP). Mice deficient in Gal-3 (Gal-3 KO) are more resistant to sepsis induced by CLP, showing lower levels of biochemical markers and neutrophil infiltration for organ injury/dysfunction than those observed in wild-type mice (WT). Furthermore, Gal-3 KO mice show an increased number of neutrophils in the primary focus of infection and reduced bacterial loads in the peritoneal cavity, blood, and lungs. Mechanistically, blood neutrophils from septic mice show higher levels of surface-bound Gal-3 than neutrophils from naive mice. The deficiency of Gal-3 was associated with increased rolling and adhesion of these cells in mesenteric venules. Our results indicate that Gal-3, secreted during sepsis, inhibits neutrophil migration into the infectious focus, which promotes the bacterial spread and worsens the outcome of sepsis.

Introduction

Sepsis is an overwhelming systemic inflammation resulting from an uncontrolled host reaction to infection that causes extensive tissue damage, organ dysfunction and can lead to death.1 Despite extensive research in this field, the current treatments for sepsis are antibiotics and supportive care.2, 3 A major hallmark of sepsis is the staggering systemic inflammation that is triggered by bacterial products.3, 4, 5 However, there is a growing body of evidence showing that endogenous host molecules released in response to tissue damage, called alarmins, also contribute to the overt inflammatory response observed during sepsis.3, 6 Therefore, the identification of alarmins and their pathophysiological actions may provide a new target for the development of therapeutic agents able to improve sepsis outcome.

Galectin-3 (Gal-3) is a member of the galectin family widely expressed in mammalian tissues that display several immune modulatory activities.7 Gal-3 can be released either passively from dead cells or through active secretion in response to inflammatory stimuli by a non-classical secretory pathway.8 Increased concentration of Gal-3 was detected in the blood of septic patients, which were associated with more severity and poor prognosis for sepsis.9, 10 However, the exact functions of Gal-3 in sepsis have not been clearly investigated. In the present study, using the well-established cecal ligation and puncture (CLP) model of sepsis, we investigated the role of Gal-3 in sepsis outcome. Our results demonstrate that Gal-3 plays a negative role in response to sepsis by limiting leukocyte trafficking to inflammatory sites.

Section snippets

Animals

All strains of mice used in this study were on the C57BL/6 background. Wild-type mice (WT) were bred in pathogen-free conditions in the animal facility of the Ribeirão Preto Medical School at the University of São Paulo. Gal-3 deficient mice (Gal-3 KO) were bred in pathogen-free conditions in the animal facility of the Ribeirão Preto Pharmaceutical Sciences School at the University of São Paulo. All mice were bred in temperature-controlled rooms (22–25 C°), with access to water and food ad

Gal-3 serum concentration is elevated in septic shock patients and severe experimental sepsis

To evaluate whether Gal-3 plays a role in the outcome of sepsis, we initially evaluated the concentration of Gal-3 in the blood serum of patients with sepsis or septic shock. We found higher Gal-3 concentration in the blood serum of patients with septic shock in relation to patients with sepsis or healthy donors. There was no difference in Gal-3 levels between patients with sepsis or healthy donor (Fig. 1A). Next, we investigate the role of Gal-3 in sepsis outcome using the CLP procedure, which

Discussion

Gal-3 is a pleiotropic glycan-binding protein involved in several physiological and pathological events. This endogenous lectin has a particular structure with a C-terminal domain in which it is a carbohydrate-recognition domain (CRD) and an N-terminal non-lectin domain associated to its oligomerization or binding to other molecules including host proteins and microbial structures.22, 23 This chimeric structure favors the ability of many Gal-3 functions in infections and inflammatory diseases,

Competing interests

The authors declare they have no competing interests that might influence the results and discussion reported in this paper.

Acknowledgments

The study was supported by grants from the São Paulo Research Foundation (FAPESP) under grant agreements n° 2011/19670-0 (Projeto Temático) and 2013/08216-2 (Center for Research in Inflammatory Disease).

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