A critical role for plasminogen in inflammation.

Plasminogen and its active form, plasmin, have diverse functions related to the inflammatory response in mammals. Due to these roles in inflammation, plasminogen has been implicated in the progression of a wide range of diseases with an inflammatory component. In this review, we discuss the functions of plasminogen in inflammatory regulation and how this system plays a role in the pathogenesis of diseases spanning organ systems throughout the body.

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

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.

Inflaming the Brain.

Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini et al. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.

Blood-derived plasminogen drives brain inflammation and plaque deposition in a mouse model of Alzheimer's disease.

Two of the most predominant features of the Alzheimer's disease (AD) brain are deposition of ß-amyloid (Aß) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of Aß. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain's immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.