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Baricitinib and Infliximab Mitigate the Endothelial-to-Mesenchymal Transition (EndMT) Induced by Cytokines in HUVECs
Amelia Barilli1, Rossana Visigalli1, Giulia Recchia Luciani1
1Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy.
Insights
SARS-CoV-2 Spike S1 peptide fragments trigger endothelial-to-mesenchymal transition (EndMT) via macrophage-secreted cytokines. Infliximab and baricitinib effectively prevent and reverse EndMT, protecting against vascular damage.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Endothelial-to-mesenchymal transition (EndMT) is implicated in various diseases, including cardiovascular and fibrotic conditions.
- COVID-19 is linked to microvascular damage and long COVID, with recent evidence suggesting SARS-CoV-2 peptide fragments induce EndMT.
Purpose of the Study:
- To investigate the immune-mediated effects of SARS-CoV-2 Spike S1 on EndMT.
- To determine if cytokines secreted by S1-activated macrophages induce EndMT in human umbilical vein endothelial cells (HUVECs).
- To evaluate the therapeutic potential of infliximab and baricitinib in preventing or reversing S1-induced EndMT.
Main Methods:
- Activation of macrophages with SARS-CoV-2 Spike S1 peptide.
- Collection and analysis of cytokines secreted by activated macrophages (focusing on TNFα and IFNγ).
- Treatment of HUVECs with macrophage-secreted cytokines to induce EndMT.
- Assessment of phenotypic changes in HUVECs, including morphology, endothelial markers (vWF, CD31, VE-cadherin), and mesenchymal markers (N-cadherin, FSP1).
- Evaluation of the combined effect of infliximab (anti-TNFα) and baricitinib (JAK-STAT inhibitor) on preventing/reversing EndMT.
Main Results:
- Cytokines secreted by S1-activated macrophages, primarily TNFα + IFNγ, induced EndMT in HUVECs.
- Induced EndMT involved loss of cobblestone morphology, reduced endothelial markers, and increased mesenchymal markers.
- Combined infliximab and baricitinib treatment effectively hindered EndMT, restoring endothelial marker expression.
- Therapeutic effects were observed even when drugs were administered after EndMT initiation.
Conclusions:
- COVID-19-associated cytokine storm plays a significant role in endothelial dysfunction and fibrotic processes.
- The findings support the clinical relevance of infliximab and baricitinib for preventing and treating vascular damage in COVID-19 and potentially other EndMT-related pathologies.
Abstract:
Endothelial-to-mesenchymal transition (EndMT) is associated with various pathologies including cardiovascular, inflammatory, and fibrotic diseases or neoplasia. Concerning COVID-19, multiple organ dysfunctions and long COVID syndrome are mediated by microvascular damage and, recently, the role of SARS-CoV-2 peptide fragments in the induction of EndMT was demonstrated. Here, we investigated the immune-mediated effects of Spike S1 of SARS-CoV-2 on EndMT and demonstrated that cytokines secreted by S1-activated macrophages, mainly TNFα + IFNγ, also induce the phenotypical switch in HUVECs. In particular, a loss of the typical cobblestone morphology is observed, along with a huge reduction in endothelial adhesion molecules, such as vWF, CD31, and VE-cadherin, and a concomitant acquisition of mesenchymal markers, such as N-cadherin and FSP1 protein. In addition, the combined use of the drug infliximab, targeting TNFα, and baricitinib, an inhibitor of the JAK-STAT pathway, hinders the phenotypical changes by restoring the proper expression of endothelial markers. The protective effect of these drugs is evident not only when they are added to the culture medium together with the trigger, but also when added later, i.e., once EndMT has been started. These findings reinforce the role of COVID-19-associated cytokine storm in endothelial dysfunction and in the onset of the fibrotic process and sustain the clinical relevance of infliximab and baricitinib for the prevention of vascular damage.
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