New research reveals how fluoxetine boosts immune protection and prevents sepsis-related heart and metabolic damage.
Study: Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality. Image Credit: luchschenF/Shutterstock.com
In a recent study published in Science Advances, researchers showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), promotes metabolic defenses to protect from sepsis-induced death.
Background
Sepsis is a life-threatening condition caused by a dysregulated response to infection. Several trials have been performed to target pro-inflammatory cytokines using neutralizing antibodies, albeit they achieved little success.
Possible reasons for the poor success of this strategy are that it renders patients immunocompromised, which makes them susceptible to secondary infections, and the timing of intervention, which is critical and must be initiated before damage occurs.
SSRIs are among the most widely prescribed drugs. Originally developed to prevent serotonin reuptake in the synaptic cleft, SSRIs have diverse peripheral effects, including metabolic and immune process regulation.
Besides, SSRIs have been demonstrated to protect from sepsis in animals, and improve outcomes in coronavirus disease 2019 (COVID-19) patients.
The study and findings
In the present study, researchers investigated how fluoxetine, an SSRI, regulates disease progression and survival in a mouse model of sepsis.
First, they explored the prophylactic effects of fluoxetine by pretreating mice with fluoxetine and challenging them with a polymicrobial sepsis model comprising Staphylococcus aureus and Escherichia coli. They noted that pretreatment was protective against infection-induced death.
Pretreatment also protects from clinical disease signs, including hypothermia and morbidity. Conversely, therapeutic administration of fluoxetine to infected mice was not protective. Moreover, both fluoxetine- and vehicle-pretreated, infected mice showed a similar increase in Troponin I, a cardiac muscle damage biomarker.
However, fluoxetine-pretreated animals had lower levels of other markers of cardiac damage, such as brain natriuretic peptide (BNP), a heart failure biomarker, and creatine kinase, a biomarker for skeletal and cardiac muscle damage.
Fluoxetine pretreatment also protected mice from kidney and liver damage. Fluoxetine-pretreated mice showed significantly reduced pathogen burden in their lungs, spleen, liver, and kidneys, but not the heart.
Next, the team measured serotonin levels in wild-type mice relative to tryptophan hydroxylase 1-/- (Tph1-/-) mice lacking peripheral serotonin. Wild-type mice showed lower serotonin levels in the heart, liver, lungs, and spleen compared to Tph1-/- mice.
Additional experiments indicated that fluoxetine-mediated protection from sepsis was independent of peripheral serotonin.
Further, two hours post-infection, fluoxetine-pretreated mice had significantly higher hepatic and circulating levels of interleukin-10 (IL-10) than vehicle-pretreated mice.
Next, the team found that the anti-inflammatory effects of fluoxetine pretreatment were abrogated in mice lacking IL-10 (Il10-/- mice). Besides, Il10-/- mice were not protected from sepsis-induced morbidity, with protection from death reduced by 70%.
Moreover, infected, wild-type mice showed increased levels of serum triglycerides, whereas fluoxetine-pretreated, infected mice showed comparable levels as infection-naïve mice. Next, the researchers examined whether hepatic triglyceride export during infection was affected by fluoxetine pretreatment.
To this end, pretreated, infected mice were administered Pluronic F-127, which inhibits lipoprotein lipase (LPL), and serum triglyceride levels were measured.
Fluoxetine recipients showed a slight, insignificant decrease in triglycerides four hours after Pluronic F-127 administration.
The team also observed that fluoxetine pretreatment elevated the peripheral uptake of triglycerides, which was necessary to protect from infection-induced morbidity and death. Next, the researchers investigated whether IL-10 production was essential to maintain triglyceride levels during sepsis.
While non-infected mice showed no differences in triglyceride levels, fluoxetine-pretreated, infected Il10-/- mice had significantly increased levels of triglycerides compared to wild-type counterparts.
Moreover, fluoxetine-pretreated, infected Il10-/- mice were less lipid-tolerant than their wild-type counterparts. The team explored how fluoxetine protects from organ damage and dysfunction.
To this end, they focused on the heart, as fluoxetine recipients were protected from higher BNP levels.
They noted that fluoxetine pretreatment protected mice from ectopic triglyceride accumulation in the heart, with no differences in the levels of active acetyl coenzyme A carboxylase 1/2, a critical regulator of fatty acid oxidation (FAO), across treatment groups.
Besides, there were no changes in the expression of FAO genes in the hearts of vehicle- and fluoxetine-pretreated, infected mice.
Finally, the team leveraged stable isotope metabolomics to examine glucose oxidation levels in the heart and profiled tricarboxylic acid (TCA) intermediates in fluoxetine- and vehicle-pretreated infected and non-infected mice.
There were significantly lower levels of labeled TCA intermediates in vehicle-pretreated, infected mice than in non-infected counterparts.
In contrast, fluoxetine-pretreated, infected animals showed similar levels of labeled TCA intermediates as non-infected controls, suggesting that fluoxetine pretreatment protected from sepsis-induced glucose oxidation impairment in the heart.
Conclusions
The study demonstrated that fluoxetine acts as a prophylactic agent promoting survival in a mouse model of sepsis. Moreover, the protective effects were associated with a decrease in total pathogen burden in the lungs, kidneys, spleen, and liver.
Together, the findings reveal the beneficial off-target effects of fluoxetine and the underlying protective immunometabolic mechanism.
Curcumin-based therapy offers hope against antibiotic-resistant superbugs