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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 3  |  Page : 88-90

Liver: Could it lead us to a promised land to deflame the brain?


Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission28-Sep-2021
Date of Decision28-Sep-2021
Date of Acceptance28-Sep-2021
Date of Web Publication22-Oct-2021

Correspondence Address:
Ho Jun Yun
Department of Neurosurgery, Wayne State University School of Medicine, 540 E, Canfield, Detroit 48201, MI
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ed.ed_20_21

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  Abstract 


Ischemic stroke occurs with disruption of blood perfusion to the brain. Damages from ischemia result in inflammation of the brain cells. Biologics and immunomodulators have been developed to mitigate neuroinflammation after ischemic stroke. Several druggable targets have been identified, including microglia/macrophages, receptors of the complement pathway, inhibition of tumor necrosis factor-ɑ, and others. However, the efficacy of the immunomodulators is in their infant stage largely due to our incomplete understanding of neuroinflammation. Hypothermia has been utilized to alleviate systemic inflammation though its negative effects have been reported. The roles of the liver in systemic inflammation and its association to ischemic stroke are fairly well-known. Local hypothermic induction to the liver may be a desirable treatment option for ischemic stroke while minimizing the systemic side effects of hypothermia. In this mini-review, we briefly summarize the current understanding of the involvement of active inflammatory response in ischemic stroke and the associated organs, particularly the liver.

Keywords: Hypothermia, immunomodulators, ischemic stroke


How to cite this article:
Yun HJ, Ding Y. Liver: Could it lead us to a promised land to deflame the brain?. Environ Dis 2021;6:88-90

How to cite this URL:
Yun HJ, Ding Y. Liver: Could it lead us to a promised land to deflame the brain?. Environ Dis [serial online] 2021 [cited 2021 Nov 29];6:88-90. Available from: http://www.environmentmed.org/text.asp?2021/6/3/88/329040




  Introduction Top


Ischemic stroke results from a disrupted cerebral blood perfusion. Recovery from ischemic stroke is challenging because nerve tissues regenerate poorly once damaged. The principles of treating stroke largely emphasize salvaging viable brain tissues during ischemia, preventing recovery complications after an ischemic injury, and minimizing vascular risk factors to prevent a future ischemic event. The current stroke therapies are based on our understanding of the underlying vascular pathology.

Over the last decades, biologics and immunomodulators have gained popularity in treating numerous diseases. Ischemic stroke was not an exception and researchers have attempted to identify inflammatory mechanisms of damaged brain tissue. Although our understanding of neuroinflammation is incomplete, the effort has led to new treatment modalities for cerebral ischemia. At this point, stroke is no longer a vascular disease. Active inflammatory mechanisms are involved in ischemic stroke and potentially affect other organs, such as the liver.


  Immunomodulators Top


Various immunomodulators have been developed to target stroke-induced neuroinflammation. For instance, minocycline and edaravone were introduced as agents modifying the functions of microglia/macrophages. Inflammatory effects of microglia/macrophages after an ischemic stroke were well-documented and their pro- and anti-inflammatory actions had been explained with M1/M2 phenotypes which controlled the production of cytokines.[1] A randomized single-blinded open-label study demonstrated that minocycline significantly improved clinical outcomes.[2] However, a subsequent multicenter prospective randomized blinded study failed to show the efficacy of minocycline.[3] Apparently, more understanding of the M1/M2 phenotypes and differences between resident microglia and circulating macrophages in ischemic stroke was needed to produce an efficacious therapeutic agent.

Receptors of the complement pathway were believed to be expressed only by immune cells. However, they have been found on neurons, microglia, and astrocytes.[4] Alawieh et al.[5] showed that CR2-Crry, an inhibitor of all complement pathways, and CR2-fH, or an inhibitor of the alternative pathway, significantly reduced apoptosis cell death, infarct size, and neurological deficits after a transient middle cerebral artery occlusion. Zhao et al.[6] explained that tissue plasminogen activator (tPA) upregulates complement cascade activity via plasmin-mediated cleavage of the C3 protein in ischemic stroke. C3a anaphylatoxin induced intracerebral hemorrhage and edema after ischemic stroke and inhibiting C3a receptors could nullify the adverse effects. The clinical use of C3a receptor inhibitors as adjuncts to tPA is limited due to the risk of hemorrhagic conversion.

Tumor necrosis factor (TNF)-α is found in the serum and cerebrospinal fluid after ischemic stroke and the levels of TNF-α correlate with severity of neurological deficit and infarct size.[7] Inhibiting TNF-α shows neuroprotective effects against ischemic injury.[8] Wang et al.[9] note that monoclonal antibodies (e.g., etanercept) could inhibit inflammation and downregulate RNA transcription of the inflammatory factors by suppressing p38 mitogen-activated protein kinase and nuclear factor-κB. Unfortunately, there have been no clinical trials testing TNF-α in ischemic stroke.

Other immunomodulators under rigorous investigations target different areas of inflammation after ischemic stroke: inhibition of the inducible nitric oxide synthase, antagonizing interleukin (IL)-1 receptor, inhibition of matrix metalloproteinase-9, inhibition of CXCL8, deletion of CCR2 and CX3CR1 receptors, anti-ICAM-1 antibody, anti-CD11b antibody, depletion of T-cells (both CD4+ and CD8+ subtypes), and promoting regulatory T-cells.


  Hypothermia and the Liver Top


The clinical efficacy of immunomodulators for ischemic stroke is still in its infant stage as shown by the mixed clinical findings. The inflammatory mechanisms underlying ischemic stroke provide vast opportunities and druggable targets for future therapies. Nevertheless, we should be reminded of the intricacy of the inflammatory process, and altering a single inflammatory factor would not bring all the desired effects we hope. Just consider the fact that the action of TNF-α depends on timing and location: TNF-α promotes cerebral edema, blood–brain barrier breakdown, and leukocyte infiltration in the early stage of stroke whereas microvasculature and neuronal repair regulation in the later stage and its neurodegenerative effect in the striatum as opposed to neuroprotection in the hippocampus.[10]

This is why hypothermic induction may shine as an alternative therapy to immunomodulators. Injured brain tissues are associated with activation of glial cells, microglia, astrocytes, infiltration of leukocytes, and secretion of immune mediators, such as IL-1, TNF, IL-10, cytokines, and chemokines.[11] Hypothermic induction tones down the systemic inflammation and globally reduces the inflammatory response without drastically disrupting the balances of many components of the neuroinflammation. In fact, hypothermia has been confirmed to be safe with intravenous thrombolysis in ischemic stroke.[12] Nevertheless, its clinical use and efficacy are limited because of increased pneumonia incidence and mortality associated with hypothermic induction.[12],[13]

This is where the liver could play pivotal roles in controlling stroke-induced inflammation. The liver produces acute phase proteins, including C-reactive protein, serum amyloid proteins, and complements, in response to anti-inflammatory cytokines, such as IL-1, IL-6, and TNF. Villapol[14] describes the roles of the liver in contributing chemokines with its highest number of macrophages, especially after brain injury. Campbell et al.[15] demonstrate how the liver, in return, may affect the brain by detecting NF-ᴋB activation highly localized around the site of an IL-1B-induced lesion in the brain; NF-ᴋB activation is not found in organs, such as the gut, heart, and kidney but throughout the liver. Furthermore, neutrophil recruitment in the brain is inhibited by adenoviral delivery of IᴋB-α super-repressor, which is mainly expressed in the liver. These findings indicate interactive responses between the brain and the liver after ischemic stroke and how the liver potentially carries valuable roles in controlling stroke-induced inflammation.


  Conclusion Top


Ischemic stroke is not a mere vascular disease in the brain. The available data for the use of immunomodulators are still premature to be utilized effectively. While further studies are being undertaken to elucidate the details of stroke-induced inflammation in search of more viable therapies, we could benefit from hypothermia, perhaps, induced locally. If cooling the entire body is cumbersome, why not just the liver? Knowing its roles in response to inflammation, we should not neglect the chances that the liver may offer to potentially deflame injured brain tissues.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Xu X, Jiang Y. The Yin and Yang of innate immunity in stroke. Biomed Res Int 2014;2014:807978.  Back to cited text no. 1
    
2.
Padma Srivastava MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, et al. Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebo-controlled trial. Neurol India 2012;60:23-8.  Back to cited text no. 2
    
3.
Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, et al. Intravenous minocycline in acute stroke: A randomized, controlled pilot study and meta-analysis. Stroke 2013;44:2493-9.  Back to cited text no. 3
    
4.
Alawieh A, Elvington A, Tomlinson S. Complement in the homeostatic and ischemic brain. Front Immunol 2015;6:417.  Back to cited text no. 4
    
5.
Alawieh A, Elvington A, Zhu H, Yu J, Kindy MS, Atkinson C, et al. Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement. J Neuroinflammation 2015;12:247.  Back to cited text no. 5
    
6.
Zhao XJ, Larkin TM, Lauver MA, Ahmad S, Ducruet AF. Tissue plasminogen activator mediates deleterious complement cascade activation in stroke. PLoS One 2017;12:e0180822.  Back to cited text no. 6
    
7.
Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 2012;32:1677-98.  Back to cited text no. 7
    
8.
Chiba T, Umegaki K. Pivotal roles of monocytes/macrophages in stroke. Mediators Inflamm 2013;2013:759103.  Back to cited text no. 8
    
9.
Wang YX, You Q, Su WL, Li Q, Hu ZQ, Wang ZG, et al. A study on inhibition of inflammation via p75TNFR signaling pathway activation in mice with traumatic brain injury. J Surg Res 2013;182:127-33.  Back to cited text no. 9
    
10.
Sriram K, O'Callaghan JP. Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol 2007;2:140-53.  Back to cited text no. 10
    
11.
Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Front Neurol 2013;4:18.  Back to cited text no. 11
    
12.
Lyden P, Hemmen T, Grotta J, Rapp K, Ernstrom K, Rzesiewicz T, et al. Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 2016;47:2888-95.  Back to cited text no. 12
    
13.
Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): Final results. Stroke 2010;41:2265-70.  Back to cited text no. 13
    
14.
Villapol S. Consequences of hepatic damage after traumatic brain injury: Current outlook and potential therapeutic targets. Neural Regen Res 2016;11:226-7.  Back to cited text no. 14
[PUBMED]  [Full text]  
15.
Campbell SJ, Anthony DC, Oakley F, Carlsen H, Elsharkawy AM, Blomhoff R, et al. Hepatic nuclear factor kappa B regulates neutrophil recruitment to the injured brain. J Neuropathol Exp Neurol 2008;67:223-30.  Back to cited text no. 15
    




 

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Abstract
Introduction
Immunomodulators
Hypothermia and ...
Conclusion
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