Glial cells as central players in neuroinflammation and neuronal damage caused by bacterial pneumonia

Pneumonia is an infection that affects the alveolar spaces of the lungs, associated with high global mortality, and remains a significant public health challenge worldwide. In a compromised immune system, the infection can progress, leading to the establishment of pneumonia. During this process, an intense inflammatory response is triggered in the lungs through the activation of resident immune cells, especially alveolar macrophages. This activation promotes the recruitment of neutrophils and the release of proinflammatory cytokines, ultimately resulting in the formation of exudative infiltrates within the alveoli. Pneumonia is a leading cause of sepsis, particularly among hospitalized patients and in intensive care units. Sepsis represents one of the most severe complications of pneumonia and is characterized by a dysregulated systemic inflammatory response to lung infection. Another critical challenge to treating clinical infectious conditions, which can lead to life-threatening sepsis, septic shock, and multi-organ dysfunction, is the continuous growth of antimicrobial resistance (AMR) in bacteria. Among the organ dysfunctions associated with sepsis, sepsis-associated encephalopathy (SAE) is the most frequent and constitutes a primary contributor to the neurological alterations observed in critically ill patients. Although SAE is often classified as a fully reversible pathophysiological process, increasing evidence suggests an association between sepsis, structural brain injury, and long-term neurological sequelae. The central nervous system (CNS) is one of the first regions exposed to peripheral inflammation during sepsis, allowing inflammatory mediators and immune cells to infiltrate the brain. This process activates microglia, the resident immune cells of the CNS, exposing neurons to an oxidative stress–rich environment that leads to neuronal dysfunction and apoptosis. A dysregulated proinflammatory microglial response plays a significant role in SAE, as microglia-derived cytokines are strongly associated with neuronal damage. Furthermore, activated microglia stimulate astrocytes to adopt a reactive inflammatory phenotype, thereby amplifying neuroinflammation. Recent studies have demonstrated that regulating microglial and astrocytic hyperactivation can attenuate the inflammatory response. Therefore, targeting glial cells during SAE holds significant therapeutic potential, offering a promising avenue for the development of new strategies aimed at reversing the exacerbated CNS inflammatory response, mitigating neuronal damage, and ultimately reducing the long-term neurological sequelae observed in post-septic patients.