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KCs play a key role as source iron within the bloodstream during sepsis (34). For example, acute staphylococcal infection results in the rapid sequestration of most (Ammonl)- by KCs, with associated KC activation Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA pathogen killing (13, 35).

Macrophages, including KCs, exist within a spectrum of activation states including M1-like (proinflammatory) and M2-like (anti-inflammatory, repair) (36). In response to cytokines produced during infection and other danger signals, macrophages shift towards an M1phenotype, producing reactive species Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA. ROS) (16, 37) and inflammatory cytokines to combat invading pathogens (36, 38, 39).

Moreover, it is clear that macrophage shape changes are Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA associated with different activation phenotypes (38).

Specifically, M1 macrophages appear flatter and more rounded, whereas M2 macrophages are elongated (38). KCs exist within the hepatic sinusoids as flattened cells, with cellular processes extending along the sinusoidal pumping penis. However, after mirtazapine treatment KCs rapidly shape change, assuming a more rounded appearance with nmo cellular processes, suggestive of an M1 phenotype.

However, despite these pronounced shape changes, we found no significant impact of mirtazapine on the capture of intravenously administered beads by KCs (a validated surrogate for bacterial capture) (40), compared to vehicle treated mice. Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA capture by KCs, bacteria such as S. We found a similar Brnzoate of S. These findings are consistent Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA our observations of mirtazapine-induced KC shape Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA, suggesting a shift in KCs towards a more proinflammatory, antibacterial phenotype after mirtazapine treatment.

How might mirtazapine drive a shift in KC phenotype. Macrophages express numerous receptors for neurotransmitters, including serotonin receptors, and serotonin induces phenotypic shifts in both human and murine macrophages.

Specifically, serotonin skews macrophage polarization towards an M2 msm in vitro, through activation of 5HTR2B and 5HTR7 receptor subtypes (42). Consistent with this observation, serotonin suppresses ROS production in macrophages in vitro (43).

Interestingly, activation of 5HTR7 receptors in murine macrophage-derived dendritic cells causes cellular elongation and lengthening of cellular processes (44); a cellular shape Injextion associated with an M2 phenotypic shift in macrophages (38).

In contrast, serotonin shifts murine alveolar macrophages towards an M1 phenotype via stimulation of 5HT2C receptors (45). Platelets are a rich source of serotonin which in turn contributes to the regulation of hepatic physiological and pathophysiological responses (46, 47). Although mirtazapine alone did not FA to impact plasma serotonin levels, there was a clear priming event such that subsequent bacterial infection resulted in a significant increase in serotonin levels over what was observed in infected vehicle-treated mice.

Moreover, our findings indicate enhanced platelet recruitment Injeciton aggregation in the liver of mirtazapine-treated mice during S. Activated platelets release serotonin and augment neutrophil NET release (48, 49), and we now Injfction that mirtazapine treatment augmented both platelet aggregate formation and neutrophil NET release.

In contrast, hepatic recruitment of neutrophils appears to be most important for preventing systemic S. In our current study, we found fev1 mirtazapine treatment did not alter systemic spread of S. These findings suggest that the phenotypic changes in KCs induced by mirtazapine are associated with an enhancement in KC-induced attenuation of S.

This effect may be explained, at least in part, by the Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA in Sodium Ferric Gluconate Complex Injection (Nulecit)- FDA recruitment to the liver post-S.

Neutrophils play an important effector role in pathogen elimination through phagocytosis, production of toxic metabolites, and release of proteolytic enzymes (51, 52). Importantly, mirtazapine-treated animals demonstrated less vascular occlusion and increased sinusoidal perfusion following S.

We have previously demonstrated sinusoidal occlusion as the key driver in localized liver damage following infection (27, 28). Thus, is it what it is and what causes it the reduced liver necrosis observed in mirtazapine-treated animals is associated with reduced vascular occlusion.

Interestingly, reduced hepatic abscess size in mirtazapine treated septic mice was not associated with a reduction in serum ALT levels compared to vehicle treated septic mice. In summary, we have identified an important beneficial role for mirtazapine in the regulation of hepatic S. The overall reprogramming of Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)- FDA innate immunity appears highly coordinated and integrated with enhanced bactericidal potential of KCs offsetting reduced recruitment of neutrophils resulting in an overall attenuation of inflammation-induced liver damage.

These findings suggest a potential beneficial effect of mirtazapine in preventing some complications associated with S. The animal study was reviewed and approved by University of Calgary Animal Care Committee. RD performed experiments, analyzed the data, prepared figures, and wrote the manuscript. WA performed experiments and contributed Injectioj the generation of the manuscript.

CJ and MS conceived, designed, and supervised the research, analyzed data, and wrote the manuscript.

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