Astroglia in Sepsis Associated Encephalopathy

Abstract

Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.

Keywords: Asrtogliopathy; Astrocyte reactivity; Astroglia; Blood brain barrier; Infection; Sepsis associated encephalopathy; Sepsis signalling.

Fig. 1

Astrocytes in the formation of brain microabscess during SAE. Infiltration of brain parenchyma by infectious agents in SAE leads to the formation of microabscesses. The abscess core contains germs and purulent exudate, surrounded by hematogenous polymorphonuclear leukocytes (PMNc). a Infiltration of germs and endotoxins triggers astroglial activation; reactive astrocytes form a dense protective border composed of their tightly coupled and overlapping processes and the extracellular matrix, which prevents the spread of microbes and inflammatory cells toward the surrounding tissue. A lesser degree of tissue damage is manifested in the form of less pronounced tissue oedema and less changes in neurones. b Astroglial asthenia and compromised astroglial reactivity facilitate abscess enlargement. Polymorphonuclear leukocytes spread freely to the adjacent parenchyma and convey damage, aggravating leakage of the BBB. Astrocytes become oedematous, undergo clazmatodendrosis, loss of functions thus leading to acute perifocal parenchymal oedema of cytotoxic or combined type. Secondary acute swelling of neurones develops, followed by their karyocytolysis. c Astroglial scar formation establishes protective wall localising the infectious lesion and thus protecting the brain parenchyma

Fig. 2

Tissue reactivity in non-disruptive BBB changes during mild systemic inflammation. Non-disruptive BBB changes are represented by functional changes of cellular components of BBB. Thus, activation of BEC by systemic agents leads to aberrant expression of transporters, receptors and adhesion molecules and production of various cytokines that stimulate cytokine receptors of other cellular constituents, in particular in astrocytes. Such stimulation causes reactive changes primarily in glia limitans. Sufficient level of astrocytic reactivity, accompanied by upregulation of cytoskeletal interfilaments GFAP and vimentin, prevents penetration of infectious and toxic agents into the brain parenchyma. BBB blood brain barrier, BEC brain endothelial cell, PVS perivascular space, rMcG ramified microglial cell, Olg oligodendrocyte

Fig. 3

Tissue reactivity in disruptive BBB changes during severe systemic inflammation. Disruptive BBB changes are represented by functional and anatomical changes of all its components. Activation of BEC by systemic agents leads both to upreglation of transporters, receptors and adhesion molecules and production of various cytokines that stimulate cytokine receptors of other cellular constituents, in particular astrocytic ones. BECs cytokines initiate reactive changes primarily in glia limitans. The list of systemic aggressive factors in septic condition, in particular hematogenious MMPs, causes alteration and destructive changes of endothelial TJ. Together with increased pinocytosis, transcytosis and apoptotic changes in BECs all these lead to BBB become leaky and highly permeable for LPS, pathogens, various immune cells and other aggressive factors observed in sepsis. Components of glia limitans also appeared damaged and show disruptive changes. Reactive changes of astrocytes in this case are supposed to be diverse. Pathological remodeling is seems to be predominant and display various phenotypes. Astrogliotic changes can be combined with oedematous ones accompanied by loss of functions. Besides loss of homeostatic functions reactive astrocytes release a number of chemokines, cytokines, enzymes, reactive species, neurotoxins that all together lead to aggravation of neuroinflammation, tissue oedema, parenchymal cell death and further increasing of the BBB leakage. BBB blood brain barrier, PVS perivascular space, aMcG activated microglial cell, Olg oligodendrocyte

Fig. 4

Astroglial reactivity as a defining factor in pathological evolution of septic encephalopathy