Plasminogen mediates communication between the peripheral and central immune systems during systemic immune challenge with lipopolysaccharide

Abstract

Background: Systemic inflammation has been implicated in the progression of many neurodegenerative diseases and may be an important driver of the disease. Dementia and cognitive decline progress more rapidly following acute systemic infection, and systemic inflammation midlife is predictive of the degree of cognitive decline. Plasmin, the active form of the serine protease plasminogen (PLG), is a blood protein that plays physiological roles in fibrinolysis, wound healing, cell signaling, extracellular matrix degradation, and inflammatory regulation. Methods: Mice were treated with an antisense oligonucleotide to deplete liver-produced PLG prior to systemic challenge with lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria, known to induce a strong immune response in animals. Following treatment, the innate immune response in the brains of these animals was examined. Results: Mice that were PLG-deficient had dramatically reduced microgliosis and astrogliosis in their brains after LPS injection. We found that blood PLG regulates the brain's innate immune response to systemic inflammatory signaling, affecting the migration of perivascular macrophages into the brain after challenge with LPS. Conclusions: Depletion of plasma PLG with an antisense oligonucleotide dramatically reduced glial cell activation and perivascular macrophage migration into the brain following LPS injection. This study suggests a critical role for PLG in mediating communication between systemic inflammatory mediators and the brain.

A critical role for plasminogen in inflammation

“…Plasminogen and plasmin both induce microglial activation and expression of IL-1β, TNF-α, and reactive oxygen species (Min et al, 2003). When blood-derived plasminogen is knocked down at the mRNA level, microglial and astrocytic activation are decreased significantly following injection with LPS, possibly due to less migration of perivascular macrophages into the brain during LPS challenge (Baker et al, 2019). Fibrinogen can also induce microglial activation through its α M β 2 -binding motif, and blocking fibrinogen-α M β 2 interactions reduces proinflammatory microglial activation (Adams et al, 2007).…”

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…Likewise, coagulation factor V, a central mediator of hemostasis, has been previously linked to delirium pathogenesis [33]. Further, plasminogen has been shown to potentiate neuroin ammation [86,87] and Alzheimer's disease-related pathology [86], and elevated serum kininogen has been associated with depression [85]. As with complement, our data suggest a relationship between POCD and dysregulation of these in ammatory and thromboactive factors.…”

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…Likewise, coagulation factor V, a central mediator of hemostasis, has been previously linked to delirium pathogenesis [81]. Further, plasminogen has been shown to potentiate neuroinflammation [82,83] and AD-related pathology [82], and elevated serum kininogen has been associated with depression [80]. As with complement, our data provide hypothesis-generating evidence for a potential relationship between POCD and dysregulation of these inflammatory and hemostatic factors.…”