Targeting Gα13-integrin interaction ameliorates systemic inflammation
| Autor: | Can Wang, Ni Cheng, Yanyan Bai, Xiaoping Du, Yaping Zhang, M. Keegan Delaney, Randal A. Skidgel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Platelet Aggregation THP-1 Cells Anti-Inflammatory Agents General Physics and Astronomy 030204 cardiovascular system & hematology Systemic inflammation Ferric Compounds Mice 0302 clinical medicine Leukocytes Platelet THP1 cell line Mice Knockout Multidisciplinary biology Thrombosis medicine.symptom Protein Binding Signal Transduction Platelets Blood Platelets Science Integrin Primary Cell Culture Inflammation GTP-Binding Protein alpha Subunits G12-G13 General Biochemistry Genetics and Molecular Biology Article Sepsis 03 medical and health sciences Platelet Adhesiveness Chlorides Fibrinolytic Agents medicine Animals Humans business.industry Macrophages General Chemistry medicine.disease Peptide Fragments Disease Models Animal 030104 developmental biology CD18 Antigens Immunology biology.protein Nanoparticles Bacterial infection business Fibrinolytic agent |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-1723 |
| Popis: | Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα13-mediated integrin “outside-in” signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα13 knockout inhibited septic thrombosis whereas leukocyte Gα13 knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα13 knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage. Bacterial or viral infection can lead to lethal systemic inflammation and thrombosis. Here, the authors show that inhibiting integrin outside-in signaling in leukocytes and platelets alleviates inflammation/clotting and improved survival in septic mice. |
| Databáze: | OpenAIRE |
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