Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain

Abstract

Neurological dysfunction, one of the severe manifestations of sepsis in patients, is closely related to increased mortality and long-term complications in intensive care units, including sepsis-associated encephalopathy (SAE) and chronic pain. The underlying mechanisms of these sepsis-induced neurological dysfunctions are elusive. However, it has been well established that microglia, the dominant resident immune cell in the central nervous system, play essential roles in the initiation and development of SAE and chronic pain. Microglia can be activated by inflammatory mediators, adjacent cells and neurotransmitters in the acute phase of sepsis and then induce neuronal dysfunction in the brain. With the spotlight focused on the relationship between microglia and sepsis, a deeper understanding of microglia in SAE and chronic pain can be achieved. More importantly, clarifying the mechanisms of sepsis-associated signaling pathways in microglia would shed new light on treatment strategies for SAE and chronic pain.

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

“…However, a clear relationship between dementia and infectious alterations of normal physiology is difficult to establish for several reasons. Sepsis, on the other hand, a grave condition which can be caused by several pathogens, is known to produce severe BBB dysfunction (Barichello et al, 2021 ), microglial activation (Li et al, 2020 ), acute neuroinflammation, brain injury and cerebral dysfunction (Meneses et al, 2019 ; Gu et al, 2021 ), and long-term cognitive and functional impairments (Brown, 2019 ; Rengel et al, 2019 ). This is also true for bacterial meningitis, especially in the case of neonates (Heath et al, 2011 ) and young infants (Hsu et al, 2018 ).…”

Comprehensive analysis of mRNAs, lncRNAs and circRNAs in the early phase of microglial activation

“…Overactivation of microglia and other immune cells may cause damage to neuron and endothelial cells, and furthermore deteriorate the BBB and enhance the release of reactive oxygen species, which seriously disturb brain function ( 9 ). Recent studies have verified that the suppression of microglial activation and central inflammatory responses may partially reverse the cognitive impairment caused by SAE ( 7 , 10 ). However, there is still a lack of effective treatment for SAE in the clinic, probably due to the detailed pathology of SAE having remained to be fully elucidated.…”

“…During the early phase of sepsis, brain microglial cells that function as peripheral macrophages are activated and transformed to the M1 cell type ( 5 , 6 ). Thereafter, A great number of inflammatory cytokines, including interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α), are secreted into the brain and lead to uncontrolled neuroinflammation ( 7 ). In addition, the activated astrocytes are also capable of releasing multiple types of inflammatory mediators, further facilitating the development of neuroinflammation ( 8 ).…”

NU9056, a KAT 5 Inhibitor, Treatment Alleviates Brain Dysfunction by Inhibiting NLRP3 Inflammasome Activation, Affecting Gut Microbiota, and Derived Metabolites in LPS-Treated Mice

“…Sepsis is one of the leading causes of death in intensive care units (ICU) worldwide and often causes neurological disorders, such as sepsis-associated encephalopathy (SAE). SAE is characterized by pro-inflammatory and anti-inflammatory imbalance, multiple organ dysfunction, severe nervous system disorder, and cognitive and mental dysfunction ( 1 ). Although progress has been made in drug therapy and surgical treatment, and age-standardized morbidity and mortality rates have been declining, patients with SAE are still severely.…”