Knockdown of endogenous circulating C1 inhibitor induces neurovascular impairment, neuroinflammation and cognitive decline

Abstract

Activation of the innate immune system, mediated by the complement and the contact systems, induces inflammation. The inhibition of these pathways by C1 inhibitor (C1INH) has been shown to decrease pro-inflammatory response and mediate vascular permeability in the periphery. However, the role of peripheral C1INH has not been associated with brain function. Using an antisense oligonucleotide (ASO) to deplete circulating liver-derived C1INH in wildtype (WT) mice, we induced the activation of the kallikrein-kinin system (KKS), which produced bradykinin in the plasma, resulting in hypotension. Interestingly, the complement system was quiescent. Depletion of liver-derived C1INH increased blood-brain barrier (BBB) permeability, increased expression of bradykinin 2 receptor, activated resident glial cells to secrete pro-inflammatory mediators such as Il-1beta, Il-6, TNF-alpha and iNOS, and induced cognitive decline. The results of this study emphasize the important role of circulating C1INH in mediating brain function through the activation of the KKS. Thus, manipulation of C1INH in neuro-vascular disorders might be therapeutically beneficial.