Targeting Gα13-integrin interaction ameliorates systemic inflammation

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 G alpha (13)-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 G alpha (13) knockout inhibited septic thrombosis whereas leukocyte G alpha (13) knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte G alpha (13) 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.

Automated summary

The study demonstrates that targeting integrin outside-in signaling in leukocytes and platelets can alleviate inflammation and clotting in septic mice, improving survival rates.