Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases.

Infectious diseases of different etiologies have been associated with acute and long-term neurological consequences. The primary cause of these consequences appears to be an inflammatory process characterized primarily by a pro-inflammatory microglial state. Microglial cells, the local effectors' cells of innate immunity, once faced by a stimulus, alter their morphology, and become a primary source of inflammatory cytokines that increase the inflammatory process of the brain. This inflammatory scenario exerts a critical role in the pathogenesis of neurodegenerative diseases. In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges. However, considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial. In this review, we discuss the relationship between infections and neurodegenerative diseases and how this may rely on microglial priming.

New perspectives for mesenchymal stromal cells as an adjuvant therapy for infectious disease-associated encephalopathies.

Knowledge of the mechanisms that trigger infection-related encephalopathies is still very limited and cell therapies are one of the most promising alternatives for neurodegenerative diseases, and its application in infectious diseases can be of great relevance. Mesenchymal stromal cells are cells with great immunomodulatory potential; therefore, their use in clinical and preclinical studies in a variety of diseases, including central nervous system diseases, increased in the last decade. Mesenchymal stromal cells can exert their beneficial effects through several mechanisms, such as direct cell contact, through surface receptors, and also through paracrine or endocrine mechanisms. The paracrine mechanism is widely accepted by the scientific community and involves the release of soluble factors, which include cytokines, chemokines and trophic factors, and extracellular vesicles. This mini review discusses mesenchymal stromal cells mechanisms of action in neurological disorders, the neuroinflammatory process that takes place in the brain as a result of peripheral inflammation and changes in the brain's cellular scenario as a common factor in central nervous system diseases, and mesenchymal stromal cells therapy in encephalopathies. Mesenchymal stromal cells have been shown to act in neuroinflammation processes, leading to improved survival and mitigating behavioral damage. More recently, these cells have been tested in preclinical models of infectious diseases-associated encephalopathies (e.g., cerebral malaria and sepsis associated encephalopathy) and have shown satisfactory results.

Infectious disease-associated encephalopathies.

Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood-brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation.

Mesenchymal Stromal Cells Protect the Blood-Brain Barrier, Reduce Astrogliosis, and Prevent Cognitive and Behavioral Alterations in Surviving Septic Mice.

OBJECTIVES: Survivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Government-affiliated research laboratory. SUBJECTS: Male Swiss Webster mice (n = 309). INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 10 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV). MEASUREMENTS AND MAIN RESULTS: At day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1ß, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1ß, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action. CONCLUSIONS: In mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.