Carbon monoxide releasing molecule-3 inhibits inflammasome activation: A potential therapy for spinal cord injury
2019; Elsevier BV; Volume: 40; Linguagem: Inglês
10.1016/j.ebiom.2019.01.020
ISSN2352-3964
Autores Tópico(s)Injury Epidemiology and Prevention
ResumoSpinal cord injury (SCI) is a devastating condition for which an approved therapy is yet to become available. Approximately 11,000 new cases of SCI occur each year [[1]Silva N.A. Sousa N. Reis R.L. Salgado A.J. From basics to clinical: a comprehensive review on spinal cord injury.Prog Neurobiol. 2014 Mar; 114 (PubMed PMID: 24269804): 25-57Crossref PubMed Scopus (525) Google Scholar], and it generally affects patients at a young age. As a result, patients find themselves having to live with the consequences of SCI for several decades. In the acute phase, current care of patients with SCI aims at surgical stabilization and decompression of the spinal cord as well as using anti-inflammatory approaches to decrease the amount of spinal cord damage [[2]Ahuja C.S. Nori S. Tetreault L. Wilson J. Kwon B. Harrop J. et al.Traumatic spinal cord injury-repair and regeneration.Neurosurgery. 2017 Mar 1; 80 (PubMed PMID: 28350947): S9-S22Crossref PubMed Scopus (382) Google Scholar]. Chronic care of patients with SCI seeks to decrease the devastating effects of comorbidities associated with the injury such as chronic pain. Despite significant improvement in the care of patients with SCI and despite the promise of new interventions such as cell-based regenerative therapies or spinal cord stimulation [[2]Ahuja C.S. Nori S. Tetreault L. Wilson J. Kwon B. Harrop J. et al.Traumatic spinal cord injury-repair and regeneration.Neurosurgery. 2017 Mar 1; 80 (PubMed PMID: 28350947): S9-S22Crossref PubMed Scopus (382) Google Scholar], there is still a significant need for more specific and efficient therapies in the care of this patient population. In a study published in EBioMedicine, Zheng and colleagues show the neuroprotective effects of carbon monoxide releasing molecule-3 (CORM3) in a compression model of thoracic spinal cord injury in rodents [[3]Zheng G. Zhan Y. Wang H. et al.Carbon monoxide releasing molecule-3 alleviates neuron death after spinal cord injury via inflammasome regulation.EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2018.12.059Summary Full Text Full Text PDF Scopus (40) Google Scholar]. Accordingly, CORM3 delivery after SCI resulted in improved histopathological and functional outcomes by decreasing inflammasome activation and the inflammasome-mediated cell death mechanism of pyroptosis. The inflammasome is a key component of the inflammatory innate immune response after SCI [[4]de Rivero Vaccari J.P. Lotocki G. Marcillo A.E. Dietrich W.D. Keane R.W. A molecular platform in neurons regulates inflammation after spinal cord injury.J Neurosci. 2008 Mar 26; 28 (PubMed PMID: 18367607): 3404-3414Crossref PubMed Scopus (273) Google Scholar]. The inflammasome is a multiprotein complex involved in the activation of the inflammatory cysteine aspartase caspase-1. Upon activation of caspase-1, this inflammatory caspase processes the pro-inflammatory cytokines interleukin(IL)-1β and IL-18. [[5]Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.Mol Cell. 2002 Aug; 10 (PubMed PMID: 12191486): 417-426Summary Full Text Full Text PDF PubMed Scopus (4208) Google Scholar] Carbon monoxide (CO) at low concentrations has been shown to be anti-inflammatory. [[6]Motterlini R. Otterbein L.E. The therapeutic potential of carbon monoxide.Nat Rev Drug Discov. 2010 Sep; 9 (PubMed PMID: 20811383): 728-743Crossref PubMed Scopus (1152) Google Scholar] Endogenous levels of CO result from the presence of haem oxygenase 2, which is constitutively expressed, and of haem oxygenase 1 enzymes, which are inducible enzymes responsible for the catabolism of haem products. Pharmaceutical-grade inhalable CO is currently under investigation in animals and humans. Previous evidence suggests a therapeutic potential for CO in conditions such as heart, lung and kidney graft rejections as well as in acute lung injury, bacterial infections, rheumatoid arthritis and myocardial infarctions, among others. In the Zheng et al. study, the authors extend our understanding of the therapeutic potential of CO by identifying the inflammasome as a target for the anti-inflammatory effects of this gas. Moreover, in such study, the authors describe the potential benefits that this approach may have for the SCI patient population. In addition to inhalable CO, it is also possible to deliver CO in the form of exogenous CO donors such as CORM1 or CORM3. Zheng et al. used CORM3 delivered immediately after SCI and showed that CORM3 inhibited the activation of the inflammatory caspases caspase-1 and caspase-11 as well as of IL-1β and IL-18. Inflammasomes are named after the pattern recognition receptors that comprised them such as the NOD-like receptors NLRP1 or NLRP3. [[7]de Rivero Vaccari J.P. Dietrich W.D. Keane R.W. Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury.J Cereb Blood Flow Metab. 2014 Mar; 34 (PubMed PMID: 24398940. Pubmed Central PMCID: 3948131): 369-375Crossref PubMed Scopus (230) Google Scholar] In the central nervous system (CNS), these receptors have been identified in neurons, astrocytes, oligodendrocytes and microglia. In the Zheng et al. study [[3]Zheng G. Zhan Y. Wang H. et al.Carbon monoxide releasing molecule-3 alleviates neuron death after spinal cord injury via inflammasome regulation.EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2018.12.059Summary Full Text Full Text PDF Scopus (40) Google Scholar], the authors show that CORM3 decreases the protein expression of NLRP1 and NLRP3 after SCI when compared to the untreated group. Taken together, these findings indicate that CORM3, and potentially inhalable CO, inhibits activation of the NLRP1 and NLRP3 inflammasomes. In the CNS, the inflammasome-mediated cell death mechanism of pyroptosis was first described in neurons [[8]Adamczak S.E. de Rivero Vaccari J.P. Dale G. Brand III, F.J. Nonner D. Bullock M.R. et al.Pyroptotic neuronal cell death mediated by the AIM2 inflammasome.J Cereb Blood Flow Metab. 2014 Apr; 34 (PubMed PMID: 24398937. Pubmed Central PMCID: 3982080): 621-629Crossref PubMed Scopus (192) Google Scholar]. More recently the substrate of pyroptosis was found to be gasdermin-D (GSDM-D). Accordingly, caspase-1 and caspase-11 cleave GSDM-D between the amino and carboxy terminal domains, which are required for pyroptosis. [[9]Shi J. Zhao Y. Wang K. Shi X. Wang Y. Huang H. et al.Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.Nature. 2015 Oct 29; 526 (PubMed PMID: 26375003): 660-665Crossref PubMed Scopus (2858) Google Scholar] In addition to inhibiting inflammasome activation after SCI, CORM3 also inhibited the expression of GSDM-D, indicating that this intervention also decreased pyroptosis. Since CORM3 is present in neurons, these findings suggest that the improved histopathological and functional outcomes reported are the results of increased neuronal survival resulting from decreased pyroptotic cell death. Thus, whereas for many years apoptosis has been the most studied cell death mechanism following CNS injury and in general, here the authors highlight the importance of targeting pyroptosis to improve outcomes after SCI. Inositol-requiring enzyme 1 (IRE1) is a transmembrane receptor activated by endoplasmic reticulum stress. IRE1 activation results in increased thioredoxin Interacting Protein (TXNIP) levels and NLRP3 inflammasome activation. [[10]Chen D. Dixon B.J. Doycheva D.M. Li B. Zhang Y. Hu Q. et al.IRE1alpha inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic-ischemic brain injury in rats.J Neuroinflammation. 2018 Feb 2; 15 (PubMed PMID: 29394934. Pubmed Central PMCID: 5797348): 32Crossref PubMed Scopus (101) Google Scholar] Zheng and colleagues show that CORM3 inhibits IRE1 phosphorylation in neurons, resulting in inflammasome inhibition, which gives a mechanistic insight as to how the inflammasome is inhibited by CORM3. In conclusion, the study of Zheng and colleagues [[3]Zheng G. Zhan Y. Wang H. et al.Carbon monoxide releasing molecule-3 alleviates neuron death after spinal cord injury via inflammasome regulation.EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2018.12.059Summary Full Text Full Text PDF Scopus (40) Google Scholar] shines light into a potential therapy for SCI patients where CO, in the form of CORM3 and – although not a part of the Zheng et al. study – inhalable CO, can be used in the treatment of SCI in order to improve histopathological and functional outcomes by inhibiting inflammasome activation and pyroptotic cell death in neurons by inhibiting the phosphorylation of IRE1. Future studies should aim to identify the therapeutic window of CORM3 as well as whether inhalable CO has a similar effect and mechanism of action in an animal model of SCI and in other conditions affecting the CNS. I am a co-founder and managing member of InflamaCORE, LLC and have patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. Carbon monoxide releasing molecule-3 alleviates neuron death after spinal cord injury via inflammasome regulationGenetic overexpression or pharmacological activation of heme oxygenase (HO) are identified as potential therapeutic target for spinal cord injury (SCI); however, the role of carbon monoxide (CO), which is a major product of haem degenerated by HO, in SCI remains unknown. Applying hemin or chemicals which may regulate HO expression or activity to increase CO production are inadequate to elaborate the direct role of CO. Here, we assessed the effect of CO releasing molecule-3 (CORM-3), the classical donor of CO, in SCI and explained its possible protective mechanism. Full-Text PDF Open Access
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