Is neuropilin-1 the neuroimmune initiator of multi-system hyperinflammation in COVID-19?

A major immunopathological feature of Coronavirus disease-2019 (COVID-19) is excessive inflammation in the form of "cytokine storm". The storm is characterized by injurious levels of cytokines which form a complicated network damaging different organs, including the lungs and the brain. The main starter of "cytokine network" hyperactivation in COVID-19 has not been discovered yet. Neuropilins (NRPs) are transmembrane proteins that act as neuronal guidance and angiogenesis modulators. The crucial function of NRPs in forming the nervous and vascular systems has been well-studied. NRP1 and NRP2 are the two identified homologs of NRP. NRP1 has been shown as a viral entry pathway for SARS-CoV2, which facilitates neuroinvasion by the virus within the central or peripheral nervous systems. These molecules directly interact with various COVID-19-related molecules, such as specific regions of the spike protein (major immune element of SARS-CoV2), vascular endothelial growth factor (VEGF) receptors, VEGFR1/2, and ANGPTL4 (regulator of vessel permeability and integrity). NRPs mainly play a role in hyperinflammatory injury of the CNS and lungs, and also the liver, kidney, pancreas, and heart in COVID-19 patients. New findings have suggested NRPs good candidates for pharmacotherapy of COVID-19. However, therapeutic targeting of NRP1 in COVID-19 is still in the preclinical phase. This review presents the implications of NRP1 in multi-organ inflammation-induced injury by SARS-CoV2 and provides insights for NRP1-targeting treatments for COVID-19 patients.