Neutrophils Return to Bloodstream Through the Brain Blood Vessel After Crosstalk With Microglia During LPS-Induced Neuroinflammation

Abstract

The circulatory neutrophil and brain tissue-resident microglia are two important immune cells involved in neuroinflammation. Since neutrophils that infiltrate through the brain vascular vessel may affect the immune function of microglia in the brain, close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and immunological aftermaths that follow. This study aimed to observe how morphology and function of both neutrophils and microglia are converted in the inflamed brain. To directly investigate cellular responses of neutrophils and microglia, LysMGFP/+ and CX3CR1GFP/+ mice were used for the observation of neutrophils and microglia, respectively. In addition, low-dose lipopolysaccharide (LPS) was utilized to induce acute inflammation in the central nervous system (CNS) of mice. Real-time observation on mice brain undergoing neuroinflammation via two-photon intravital microscopy revealed various changes in neutrophils and microglia; namely, neutrophil infiltration and movement within the brain tissue increased, while microglia displayed morphological changes suggesting an activated state. Furthermore, neutrophils seemed to not only actively interact with microglial processes but also exhibit reverse transendothelial migration (rTEM) back to the bloodstream. Thus, it may be postulated that, through crosstalk with neutrophils, macrophages are primed to initiate a neuroinflammatory immune response; also, during pathogenic events in the brain, neutrophils that engage in rTEM may deliver proinflammatory signals to peripheral organs outside the brain. Taken together, these results both show that neuroinflammation results in significant alterations in neutrophils and microglia and lay the pavement for further studies on the molecular mechanisms behind such changes.

Interplay of gut microbiota and oxidative stress: Perspective on neurodegeneration and neuroprotection

“…Reactive species like H 2 O 2 and NO . attracts microglia at the site to enforce local inflammation driving neurodegeneration [80] . Brain is prone to disrupted redox homeostasis due to modest antioxidant defense system in comparison to other tissues.…”

“…Reactive species like H 2 O 2 and NO . attracts microglia at the site to enforce local inflammation driving neurodegeneration [80] .…”

Changes in leukocytes and CRP in different stages of major depression

“…Nevertheless, these findings suggest a role of neutrophils in depression in line with the finding that transmigration of neutrophils into the brain induces depressive-like behavior in mice [ 37 ]. In line with publications on depression in the context of (prolonged) sickness behaviour [ 1 ], a study in mice treated with low-dose lipopolysaccharide (LPS) showed that transmigrating neutrophils interacted with activated microglial cells [ 38 ]. Furthermore, neutrophils not only seemed to actively interact with microglial processes but also exhibited reverse transendothelial migration back to the bloodstream.…”

Sepsis-Exacerbated Brain Dysfunction After Intracerebral Hemorrhage

“…Acute brain injury including ICH occurrence will initiate neuroinflammation and then spread inflammatory signals to the periphery, and monocyte infiltration might be a crucial mediator in this process. In an LPS-induced neuroinflammatory mouse model, the infiltrated neutrophils exhibited reverse trans-endothelial migration back to the bloodstream after interacting with microglia (Kim et al, 2020). Subsequently, these reverse-moving neutrophil-transported signals to several organs have been reported in numerous studies.…”

“…Subsequently, these reverse-moving neutrophil-transported signals to several organs have been reported in numerous studies. For example, the upregulation of inflammatory cytokines (e.g., IL-8 and IL-10) were observed in the kidney used for organ donation, resulting in the reduction of allograft survival via increasing the number of trafficking inflammatory cells (i.e., FoxP3 + regulatory T cells) (Morariu et al, 2008;Kim et al, 2020). In addition, in the brain injury models, infiltrated monocytes and macrophages were demonstrated to produce several chemoattractants (i.e., leukotriene-B4) and other cytokines (e.g., IL-1β, IL-6, and TNF-α), causing the amplification of pulmonary inflammation (Kalsotra et al, 2007;Mrozek et al, 2015).…”