Abstract
The defective eradication of invading pathogens is a major cause of death in sepsis. As professional phagocytic cells, macrophages actively engulf/kill microorganisms and play essential roles in innate immune response against pathogens. Growth differentiation factor 3 (GDF3) was previously implicated as an important modulator of inflammatory response upon acute sterile injury. In this study, administration of recombinant GDF3 protein (rGDF3) either before or after CLP surgery remarkably improved mouse survival, along with significant reductions in bacterial load, plasma pro-inflammatory cytokine levels, and organ damage. Notably, our in vitro experiments revealed that rGDF3 treatment substantially promoted macrophage phagocytosis and intracellular killing of bacteria in a dose-dependent manner. Mechanistically, RNA-seq analysis results showed that CD5L, known to be regulated by liver X receptor α (LXRα), was the most significantly upregulated gene in rGDF3-treated macrophages. Furthermore, we observed that rGDF3 could promote LXRα nuclear translocation and thereby, augmented phagocytosis activity in macrophages, which was similar as LXRα agonist GW3965 did. By contrast, pre-treating macrophages with LXRα antagonist GSK2033 abolished beneficial effects of rGDF3 in macrophages. In addition, rGDF3 treatment failed to enhance bacteria uptake and killing in LXRα-knockout (KO) macrophages. Taken together, these results uncover that GDF3 may represent a novel mediator for controlling bacterial infection.
Highlights
Sepsis is characterized as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection [1, 2]
To explore whether recombinant GDF3 protein (rGDF3) could provide a preventive effect in response to polymicrobial sepsis, WT mice were received rGDF3 (20 μg/kg body weight) or BSA vesicle via the tail vein injection 3 h prior to cecal ligation and puncture (CLP) surgery (Figure 1A), and mortality was monitored over 7 days
We found that the administration of rGDF3 significantly rescued CLP-induced lung injury, as evidenced by the decrease in neutrophil infiltration, formation of hyaline membranes, thickness of alveolar wall, and the alveolar collapse in lung tissues collected from rGDF3-treated mice, compared to those from BSA-treated mice (Figures 1C–E)
Summary
Sepsis is characterized as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection [1, 2]. Aggressive antibiotic treatments are applied to control bacterial infection at the early stage, sepsis remains a leading cause of death in intensive care units [3, 4]. There is currently lack of specific pharmacologic therapy that can target the host immune response to eradicate invading pathogens [8, 9], and drug-resistance bacteria are emerging [10]. It is urgently needed to develop alternative treatment strategies to enhance host defenses for timely clearance of bacteria [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
