Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment

Andonegui, Graciela; Zelinski, Erin L.; Schubert, Courtney Lynn; Knight, Derrice; Craig, Laura A.; Winston, Brent W.; Spanswick, Simon C.; Petri, Bjӧrn; Jenne, Craig N.; Sutherland, Janice; Nguyen, Ruby H.N.; Jayawardena, N; Kelly, Margaret M.; Doig, Christopher J.; Sutherland, Robert J.; Kubes, Paul

doi:10.1172/jci.insight.99364

Cited by 129 publications

(123 citation statements)

References 56 publications

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“…For instance, there is evidence showing that vascular leukocytes can promote changes in CNS parenchymal cells . For instance, CCR2 + inflammatory monocytes rolling and adhering in the brain vasculature during sepsis play a crucial role in the cognitive impairment and microglia activation . Thus, future studies will be necessary to evaluate whether inflammatory monocytes found in the vasculature irrigating the spinal cord after SNI are involved in the development of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Guimarães

Davoli‐Ferreira

Fonseca

et al. 2019

Journal of Leukocyte Biology

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The development of neuropathic pain after peripheral nerve injury involves neuroimmune–glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2‐deficient mice. These results suggest that blood‐circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2‐expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.

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Section: Discussionmentioning

confidence: 99%

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Guimarães

Davoli‐Ferreira

Fonseca

et al. 2019

Journal of Leukocyte Biology

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Section: Systemic Infectionsmentioning

confidence: 99%

“…The authors observed an increased recruitment of neutrophils and CCR2 + inflammatory monocytes into the brain, as well as the subtle activation of microglia. These events transpired in the absence of any bacteria detected in the brain . Interestingly, it was found that inhibiting the recruitment of monocytes, but not neutrophils, significantly reduced signs of neuroinflammation and cognitive impairment after infection .…”

Section: Systemic Infectionsmentioning

confidence: 99%

“…Notably, it has become apparent that inflammation triggered by systemic infections can negatively impact the brain and two recent studies used IVM to examine these changes after bacterial sepsis. 47,48 Plotkowski et al 48 used a Pseudomonas aeruginosa pneumonia model of sepsis and observed significant leukocyte rolling and adhesion to the cerebral vessels accompanied by impaired capillary perfusion in the brain. Moreover, they showed that these effects were primarily mediated by the release of the cytotoxin ExoU by Pseudomonas aeruginosa, which initiated an inflammatory response in the cerebral vasculature by activating the platelet-activating factor receptor pathway.…”

Section: Systemic Infections: Imaging the Brainmentioning

confidence: 99%

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Unraveling the host's immune response to infection: Seeing is believing

Scott

Sarkar

Kratofil

et al. 2019

Journal of Leukocyte Biology

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It has long been appreciated that understanding the interactions between the host and the pathogens that make us sick is critical for the prevention and treatment of disease. As antibiotics become increasingly ineffective, targeting the host and specific bacterial evasion mechanisms are becoming novel therapeutic approaches. The technology used to understand host‐pathogen interactions has dramatically advanced over the last century. We have moved away from using simple in vitro assays focused on single‐cell events to technologies that allow us to observe complex multicellular interactions in real time in live animals. Specifically, intravital microscopy (IVM) has improved our understanding of infection, from viral to bacterial to parasitic, and how the host immune system responds to these infections. Yet, at the same time it has allowed us to appreciate just how complex these interactions are and that current experimental models still have a number of limitations. In this review, we will discuss the advances in vivo IVM has brought to the study of host‐pathogen interactions, focusing primarily on bacterial infections and innate immunity.

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“…Following an episode of sepsis, patients are at a 3.3 times higher risk of developing moderate‐to‐severe neurocognitive impairment . This risk might be related to the amount of CCR2 + monocytes recruited to the CNS during acute septic episodes, highlighting the role of NI in SAE.…”

Section: Human Sepsis and Saementioning

confidence: 99%

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

Meneses

Cárdenas

Espinosa

et al. 2018

Annals of the New York Academy of Sciences

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Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation which may result in severe impairment of the central nervous system (CNS). Indeed, the ensuing blood–brain barrier disruption associated with sepsis promotes glial activation and starts a storm of proinflammatory cytokines in the CNS that leads to brain dysfunction in sepsis survivors. Endotoxic shock induced in mice by peripheral injection of lipopolysaccharides closely resembles the peripheral and central inflammation observed in sepsis. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the development of new anti‐neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors.

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Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment

Cited by 129 publications

References 56 publications

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury

Unraveling the host's immune response to infection: Seeing is believing

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

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