Abstract
Recent studies on coronavirus infectious disease 2019 (COVID-19) pathophysiology indicated the cytokine release syndrome induced by the virus as the main cause of mortality. Patients with severe COVID-19 infection present a systemic hyper inflammation that can lead to lung and multi-organ injuries. Among the most recent treatments, corticosteroids have been identified to be effective in mitigating these catastrophic effects. Our group has recently developed leukocyte-derived nanovesicles, termed leukosomes, able to target in vivo the inflamed vasculature associated with pathological conditions including cancer, cardiovascular diseases, and sepsis. Herein, to gain insights on the anti-inflammatory properties of leukosomes, we investigated their ability to reduce uncontrolled inflammation in a lethal model of lipopolysaccharide (LPS)-induced endotoxemia, recapitulating the cytokine storm syndrome observed in COVID-19 infection after encapsulating dexamethasone. Treated animals showed a significant survival advantage and an improved immune response resolution, as demonstrated by a cytokine array analysis of pro- and anti-inflammatory cytokines, chemokines, and other immune-relevant markers. Our results showed that leukosomes enhance the therapeutic activity of dexamethasone and better control the inflammatory response compared to the free drug. Such an approach could be useful for the development of personalized therapies in the treatment of hyperinflammation related to infectious diseases, including the ones caused by COVID-19.
Highlights
In December 2019, the virus causing coronavirus disease, i.e., COVID-19, was first identified in Wuhan, China
Compared to the other biomimetic approaches described above, where LPS was mechanically removed from the circulation, we demonstrated both in vitro and in vivo that the anti-inflammatory features of leukosomes are due to a direct interaction with macrophages
Considering the impact of dexamethasone in COVID-19 therapy, we tested the anti-inflammatory properties of leukosomes loaded with dexamethasone in an LPS-induced mouse model of endotoxemia that recapitulates the cytokine storm syndrome typical of some systemic infections, including the catastrophic recent one causing the COVID-19 pandemic
Summary
In December 2019, the virus causing coronavirus disease, i.e., COVID-19, was first identified in Wuhan, China. Compared to the other biomimetic approaches described above, where LPS was mechanically removed from the circulation, we demonstrated both in vitro and in vivo that the anti-inflammatory features of leukosomes are due to a direct interaction with macrophages This interaction leads to an increased release of anti-inflammatory cytokines, while reducing the pro-inflammatory ones, decreasing the systemic inflammatory response and prolonging mouse survival. It is worth noting that these anti-inflammatory properties derive from the empty carriers, without the need of a payload, which behave like anti-inflammatory exosomes, with whom they share similar size and surface charge, and comparable protein profiles, but a more potent anti-inflammatory activity [20] Based on these results, and considering the impact of dexamethasone in COVID-19 therapy, we tested the anti-inflammatory properties of leukosomes loaded with dexamethasone in an LPS-induced mouse model of endotoxemia that recapitulates the cytokine storm syndrome typical of some systemic infections, including the catastrophic recent one causing the COVID-19 pandemic. This is mainly due to the ability of DEX-LKs to reduce the expression of typical pro-inflammatory markers, such as TNF-α, IL-16 and IL-1α, and to modulate the expressions of those chemokines involved in the recruitment of T and B cells to the pulmonary tissue, exacerbating the local inflammatory response
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