NELL1 variant protein (NV1) modulates hyper-inflammation, Th-1 mediated immune response, and the HIF-1α hypoxia pathway to promote healing in viral-induced lung injury

Research underscores the urgent need for technological innovations to treat lung tissue damage from viral infections and the lasting impact of COVID-19. Our study demonstrates the effectiveness of recombinant human NV1 protein in promoting a pro-healing extracellular matrix that regulates homeostasis in response to excessive tissue reactions caused by infection and injury. NV1 achieves this by calibrating multiple biological mechanisms, including reducing hyperinflammatory cytokine levels (e.g., IFN-γ, TNF-α, IL-10, and IP-10), enhancing the production of proteins involved in viral inactivation and clearance through endocytosis and phagocytosis (e.g., IL-9, IL-1α), regulating pro-clotting and thrombolytic pathways (e.g., downregulates SERPINE 1 and I-TAC during Th1-mediated inflammation), maintaining cell survival under hypoxic conditions via HIF-1α regulation through the M3K5-JNK-AP-1 and TSC2-mTOR pathways, and promoting blood vessel formation. Our findings reveal NV1 as a potential therapeutic candidate for treating severe lung injuries caused by inflammatory and hypoxic conditions from viral infections and related diseases. •NV1-mediated ECM restores balance in tissue responses to infection and injury.•Reduces hyperinflammatory cytokines like IFN-γ, TNF-α, IL-10, and IP-10.•Increases proteins aiding viral inactivation and clearance (IL-9, IL-1α).•Controls clotting/thrombolysis by downregulating SERPINE 1, I-TAC in Th1 inflammation.•Regulates HIF-1α for cell survival and promotes blood vessel formation.