Polarization of Microglia and Its Therapeutic Potential in Sepsis

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, leaving the inflammation process without a proper resolution, leading to tissue damage and possibly sequelae. The central nervous system (CNS) is one of the first regions affected by the peripheral inflammation caused by sepsis, exposing the neurons to an environment of oxidative stress, triggering neuronal dysfunction and apoptosis. Sepsis-associated encephalopathy (SAE) is the most frequent sepsis-associated organ dysfunction, with symptoms such as deliriums, seizures, and coma, linked to increased mortality, morbidity, and cognitive disability. However, the current therapy does not avoid those patients’ symptoms, evidencing the search for a more optimal approach. Herein we focus on microglia as a prominent therapeutic target due to its multiple functions maintaining CNS homeostasis and its polarizing capabilities, stimulating and resolving neuroinflammation depending on the stimuli. Microglia polarization is a target of multiple studies involving nerve cell preservation in diseases caused or aggravated by neuroinflammation, but in sepsis, its therapeutic potential is overlooked. We highlight the peroxisome proliferator-activated receptor gamma (PPARγ) neuroprotective properties, its role in microglia polarization and inflammation resolution, and the interaction with nuclear factor-κB (NF-κB) and mitogen-activated kinases (MAPK), making PPARγ a molecular target for sepsis-related studies to come.

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

“…During sepsis, inflammatory factors and signals reach different regions of the brain through various means, such as body fluids and nerves ( 16 ). Neuroinflammation plays a vital role in the pathogenesis of SAE, as uncontrolled inflammatory responses are the main manifestations of sepsis.…”

TNFRSF6 induces mitochondrial dysfunction and microglia activation in the in vivo and in vitro models of sepsis-associated encephalopathy

“…Therefore, revealing the pathogenesis of SAE is of great significance. Microglia activation is critical to neuroinflammation and SAE development [20,21]. At present, some studies have revealed that the inhibition of microglia activation can alleviate the SAE process.…”

β-patchoulene alleviates cognitive dysfunction in a mouse model of sepsis associated encephalopathy by inhibition of microglia activation through Sirt1/Nrf2 signaling pathway

“…Activated microglial cells are very plastic and may exist in multiple phenotypes, ranging from pro-inflammatory(M1) cell population releasing nitric oxide, TNF-α and IL-1β to antiinflammatory subtype releasing IL-10 or IL-4. The proinflammatory phenotypes are usually considered to be neurotoxic whereas M2 phenotype may contribute to neuroprotection [9,10]. Consistently, the inhibition of M1 polarization by an intracerebroventicular(i.c.v) injection of minocycline suppressed the oxidative damage, neuroinflammation and long-term cognitive impairments in septic rats [11].Thus, modulation of microglia activation may provide with a promising approach in treating SAE.…”