Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

Abstract

The cross‐talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein‐kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood–brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild‐type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long‐term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro‐inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive‐like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

“…11,15,44,45 In enrichment analysis, genes related to the phenotype of IQ (SERPING1, CD46) tended to be regulators of the complement system, thus our PGS may represent regulatory activities of the complement cascade, inhibiting inappropriate activation of complement and inflammatory processes. 41,46,47 This finding was in the overall sample of healthy participants and patients, showing an association between complement and cognition irrespective of diagnosis. This is consistent with MAGMA analysis, as complement genes were enriched for the phenotype of IQ in a GWAS of healthy participants, but no enrichment of these genes for the phenotype of SZ was observed.…”

“…The direction of this association is interesting given multiple previous reports that upregulation of complement genes (theoretically driving increased neuroinflammation and synaptic pruning) to be associated with cognitive decline . In enrichment analysis, genes related to the phenotype of IQ (SERPING1, CD46) tended to be regulators of the complement system, thus our PGS may represent regulatory activities of the complement cascade, inhibiting inappropriate activation of complement and inflammatory processes . This finding was in the overall sample of healthy participants and patients, showing an association between complement and cognition irrespective of diagnosis.…”

“…SERPING1, also known as C1 inhibitor, has been suggested to participate in neuronal stem cell proliferation, and play a role in the three activation arms of the complement system . Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits . Using a shRNA‐mediated knock‐out of SERPING1 to silence the gene expression, a recent study suggests knock‐out of this gene impairs neuronal migration and affects brain development .…”

“…40 Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits. 41 Using a shRNA-mediated knock-out of SERPING1 to silence the gene expression, a recent study suggests knock-out of this gene impairs neuronal migration and affects brain development. 40 Preliminary evidence in a study of complement genes in twins with SZ implicated peripheral expression of C5 and SERPING1 to be associated with cortical thinning in the superior frontal region 4 ; SERPING1 has also been found to be overexpressed in the amygdala of patients with SZ.…”

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes

“…These mouse models do not reproduce the HAE phenotype, thus limiting its interest. Interestingly Farfara et al () knocked down circulating C1Inh in wild‐type mice to understand the effect of plasma C1Inh on brain pathology via the vascular system, with observations pertaining to former clinical observations with C1Inh deficiency described as angioneurotic edema and the role of C1Inh as a gatekeeper to the brain via the neurovascular system.…”