Research Article
Volume 17 Issue 3 - 2021
HDAC6 Inhibition Aggravates the Lyme Disease-Associated Inflammation
Meerambika Mishra, Lindsey Powers, Crystal L Vanhorn and Bikash Sahay*
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
*Corresponding Author: Bikash Sahay, Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA.
Received: July 13, 2020; Published: February 27, 2021



Abstract

Histones are basic proteins that wrap around DNA for conditional accessibility of DNA to their transcription; however, HDAC6 is a unique histone deacetylase capable of deacetylating both histone and non-histone proteins. Recently HDAC6 has been shown to play an inflammatory role by limiting p38-MAPK activation in an LPS sepsis model. Here, we tested the ability of HDAC6 inhibition to control inflammation initiated by B. burgdorferi both in vitro and in vivo. The data indicate inhibition of HDAC6 leads to an increase in pro-inflammatory cytokines in macrophages and mice. HDAC6 deficient macrophages revealed similar results when co-incubated with B. burgdorferi. Inhibition of HDAC6 also resulted in diverse responses when exposed to different TLR ligands, suggesting a more complex role of HDAC6 in the inflammatory process. Additionally, inhibition of HDAC6 led to an increased acetylation of tubulin; however, there was minimal impact on p38-MAPK phosphorylation.

Keywords: HDAC6; Tubastatin A; Borrelia; Inflammation; TLR

References

  1. Radolf JD., et al. “Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes”. Nature Reviews Microbiology 2 (2012): 87-99.
  2. Lasky CE., et al. “Macrophage Polarization during Murine Lyme Borreliosis”. Infection and Immunity 7 (2015): 2627-2635.
  3. Sonderegger FL., et al. “Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-gamma-mediated Lyme arthritis”. Journal of Immunology 3 (2012): 1381-1393.
  4. Sahay B., et al. “CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance”. PLOS Pathogens 12 (2009): e1000687.
  5. Li Y., et al. “Inhibition of histone deacetylase 6 improves long-term survival in a lethal septic model”. The Journal of Trauma and Acute Care Surgery2 (2015): 378-385.
  6. Yan B., et al. “HDAC6 deacetylase activity is critical for lipopolysaccharide-induced activation of macrophages”. PLoS One10 (2014): e110718.
  7. Wang B., et al. “Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production”. Nature Communications 5 (2014): 3479.
  8. Hawley K., et al. “Macrophage p38 mitogen-activated protein kinase activity regulates invariant natural killer T-cell responses during Borrelia burgdorferi infection”. The Journal of Infectious Diseases 2 (2012): 283-291.
  9. Sahay B., et al. “Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling”. Infection and Immunity 4 (2018): e00781.
  10. Hubbert C., et al. “HDAC6 is a microtubule-associated deacetylase”. Nature6887 (2002): 455-458.
  11. Crandall H., et al. “Gene expression profiling reveals unique pathways associated with differential severity of lyme arthritis”. Journal of Immunology 11 (2006): 7930-7942.
  12. Li Y., et al. “Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes”. The FEBS Journal 3 (2013): 775-793.
  13. Bertos NR., et al. “Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention”. Journal of Biological Chemistry 46 (2004): 48246-48254.
  14. Verdel A., et al. “Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm”. Current Biology: CB 12 (2000): 747-749.
  15. Boyault C., et al. “HDAC6-p97/VCP controlled polyubiquitin chain turnover”. The EMBO Journal 14 (2006): 3357-3366.
  16. Liu Y., et al. “Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation”. Journal of Biological Chemistry 34 (2012): 29168-29174.
  17. Fusco C., et al. “The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes the sequestration and clearance of ubiquitinated proteins into the aggresome”. PLoS One7 (2012): e40440.
  18. Cheng F., et al. “A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs”. Journal of Immunology 6 (2014): 2850-2862.
  19. Villagra A., et al. “The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance”. Nature Immunology 1 (2009): 92-100.
  20. Cheng F., et al. “Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells”. Molecular Immunology1 (2014): 44-53.
  21. Zenk SF., et al. “Role of <em>Salmonella enterica</em> Lipopolysaccharide in Activation of Dendritic Cell Functions and Bacterial Containment”. The Journal of Immunology 4 (2009): 2697-2707.
  22. Pupo E., et al. “Intact rough- and smooth-form lipopolysaccharides from Escherichia coli separated by preparative gel electrophoresis exhibit differential biologic activity in human macrophages”. The FEBS Journal 4 (2013): 1095-1111.
  23. Rittig MG., et al. “Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes”. Journal of Leukocyte Biology 6 (2003): 1045-1055.
  24. Godowski PJ. “A smooth operator for LPS responses”. Nature Immunology 6 (2005): 544-546.
  25. YL Lightfoot., et al. “Colonic Immune Suppression, Barrier Dysfunction, and Dysbiosis by Gastrointestinal Bacillus anthracis Infection”. PLoS One 9 (2014): e100532.
Citation: Bikash Sahay., et al. “HDAC6 Inhibition Aggravates the Lyme Disease-Associated Inflammation”. EC Microbiology 17.3 (2021): 77-86.

PubMed Indexed Article

EC Pharmacology and Toxicology
LC-UV-MS and MS/MS Characterize Glutathione Reactivity with Different Isomers (2,2' and 2,4' vs. 4,4') of Methylene Diphenyl-Diisocyanate.

PMID: 31143884 [PubMed]

PMCID: PMC6536005


EC Pharmacology and Toxicology
Alzheimer's Pathogenesis, Metal-Mediated Redox Stress, and Potential Nanotheranostics.

PMID: 31565701 [PubMed]

PMCID: PMC6764777


EC Neurology
Differences in Rate of Cognitive Decline and Caregiver Burden between Alzheimer's Disease and Vascular Dementia: a Retrospective Study.

PMID: 27747317 [PubMed]

PMCID: PMC5065347


EC Pharmacology and Toxicology
Will Blockchain Technology Transform Healthcare and Biomedical Sciences?

PMID: 31460519 [PubMed]

PMCID: PMC6711478


EC Pharmacology and Toxicology
Is it a Prime Time for AI-powered Virtual Drug Screening?

PMID: 30215059 [PubMed]

PMCID: PMC6133253


EC Psychology and Psychiatry
Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

PMID: 30417173 [PubMed]

PMCID: PMC6226033


EC Anaesthesia
Arrest Under Anesthesia - What was the Culprit? A Case Report.

PMID: 30264037 [PubMed]

PMCID: PMC6155992


EC Orthopaedics
Distraction Implantation. A New Technique in Total Joint Arthroplasty and Direct Skeletal Attachment.

PMID: 30198026 [PubMed]

PMCID: PMC6124505


EC Pulmonology and Respiratory Medicine
Prevalence and factors associated with self-reported chronic obstructive pulmonary disease among adults aged 40-79: the National Health and Nutrition Examination Survey (NHANES) 2007-2012.

PMID: 30294723 [PubMed]

PMCID: PMC6169793


EC Dental Science
Important Dental Fiber-Reinforced Composite Molding Compound Breakthroughs

PMID: 29285526 [PubMed]

PMCID: PMC5743211


EC Microbiology
Prevalence of Intestinal Parasites Among HIV Infected and HIV Uninfected Patients Treated at the 1o De Maio Health Centre in Maputo, Mozambique

PMID: 29911204 [PubMed]

PMCID: PMC5999047


EC Microbiology
Macrophages and the Viral Dissemination Super Highway

PMID: 26949751 [PubMed]

PMCID: PMC4774560


EC Microbiology
The Microbiome, Antibiotics, and Health of the Pediatric Population.

PMID: 27390782 [PubMed]

PMCID: PMC4933318


EC Microbiology
Reactive Oxygen Species in HIV Infection

PMID: 28580453 [PubMed]

PMCID: PMC5450819


EC Microbiology
A Review of the CD4 T Cell Contribution to Lung Infection, Inflammation and Repair with a Focus on Wheeze and Asthma in the Pediatric Population

PMID: 26280024 [PubMed]

PMCID: PMC4533840


EC Neurology
Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis

PMID: 28066845 [PubMed]

PMCID: PMC5214344


EC Pharmacology and Toxicology
Paradigm Shift is the Normal State of Pharmacology

PMID: 28936490 [PubMed]

PMCID: PMC5604476


EC Neurology
Examining those Meeting IOM Criteria Versus IOM Plus Fibromyalgia

PMID: 28713879 [PubMed]

PMCID: PMC5510658


EC Neurology
Unilateral Frontosphenoid Craniosynostosis: Case Report and a Review of the Literature

PMID: 28133641 [PubMed]

PMCID: PMC5267489


EC Ophthalmology
OCT-Angiography for Non-Invasive Monitoring of Neuronal and Vascular Structure in Mouse Retina: Implication for Characterization of Retinal Neurovascular Coupling

PMID: 29333536 [PubMed]

PMCID: PMC5766278


EC Neurology
Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

PMID: 31032493 [PubMed]

PMCID: PMC6483108


EC Microbiology
Onchocerciasis in Mozambique: An Unknown Condition for Health Professionals.

PMID: 30957099 [PubMed]

PMCID: PMC6448571


EC Nutrition
Food Insecurity among Households with and without Podoconiosis in East and West Gojjam, Ethiopia.

PMID: 30101228 [PubMed]

PMCID: PMC6086333


EC Ophthalmology
REVIEW. +2 to +3 D. Reading Glasses to Prevent Myopia.

PMID: 31080964 [PubMed]

PMCID: PMC6508883


EC Gynaecology
Biomechanical Mapping of the Female Pelvic Floor: Uterine Prolapse Versus Normal Conditions.

PMID: 31093608 [PubMed]

PMCID: PMC6513001


EC Dental Science
Fiber-Reinforced Composites: A Breakthrough in Practical Clinical Applications with Advanced Wear Resistance for Dental Materials.

PMID: 31552397 [PubMed]

PMCID: PMC6758937


EC Microbiology
Neurocysticercosis in Child Bearing Women: An Overlooked Condition in Mozambique and a Potentially Missed Diagnosis in Women Presenting with Eclampsia.

PMID: 31681909 [PubMed]

PMCID: PMC6824723


EC Microbiology
Molecular Detection of Leptospira spp. in Rodents Trapped in the Mozambique Island City, Nampula Province, Mozambique.

PMID: 31681910 [PubMed]

PMCID: PMC6824726


EC Neurology
Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases.

PMID: 31528859 [PubMed]

PMCID: PMC6746603


EC Psychology and Psychiatry
Can Chronic Consumption of Caffeine by Increasing D2/D3 Receptors Offer Benefit to Carriers of the DRD2 A1 Allele in Cocaine Abuse?

PMID: 31276119 [PubMed]

PMCID: PMC6604646


EC Anaesthesia
Real Time Locating Systems and sustainability of Perioperative Efficiency of Anesthesiologists.

PMID: 31406965 [PubMed]

PMCID: PMC6690616


EC Pharmacology and Toxicology
A Pilot STEM Curriculum Designed to Teach High School Students Concepts in Biochemical Engineering and Pharmacology.

PMID: 31517314 [PubMed]

PMCID: PMC6741290


EC Pharmacology and Toxicology
Toxic Mechanisms Underlying Motor Activity Changes Induced by a Mixture of Lead, Arsenic and Manganese.

PMID: 31633124 [PubMed]

PMCID: PMC6800226


EC Neurology
Research Volunteers' Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

PMID: 29662969 [PubMed]

PMCID: PMC5898812


EC Pharmacology and Toxicology
Hyperbaric Oxygen Therapy for Alzheimer's Disease.

PMID: 30215058 [PubMed]

PMCID: PMC6133268


News and Events

March Issue Release

We always feel pleasure to share our updates with you all. Here, notifying you that we have successfully released the March issue of respective journals and can be viewed in the current issue pages.

Submission Deadline for April Issue

Ecronicon delightfully welcomes all the authors around the globe for effective collaboration with an article submission for the April issue of respective journals. Submissions are accepted on/before March 18, 2021.

Certificate of Publication

Ecronicon honors with a "Publication Certificate" to the corresponding author by including the names of co-authors as a token of appreciation for publishing the work with our respective journals.

Best Article of the Issue

Editors of respective journals will always be very much interested in electing one Best Article after each issue release. The authors of the selected article will be honored with a "Best Article of the Issue" certificate.

Certifying for Review

Ecronicon certifies the Editors for their first review done towards the assigned article of the respective journals.

Latest Articles

The latest articles will be updated immediately on the articles in press page of the respective journals.

Immediate Assistance

The prime motto of this team is to clarify all the queries without any delay or hesitation to avoid the inconvenience. For immediate assistance on your queries please don't hesitate to drop an email to editor@ecronicon.uk