Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models

Author:

Laliberte Alex M123,Karadimas Spyridon K124,Vidal Pia M15,Satkunendrarajah Kajana1678,Fehlings Michael G124

Affiliation:

1. Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON M5T2S8, Canada

2. Institute of Medical Sciences, University of Toronto, Toronto, ON M5T2S8, Canada

3. Department of Biology, University of Ottawa, Ottawa, ON K1N6N5, Canada

4. Division of Neurosurgery, Department of Surgery, University of Toronto, ON M5T2S8, Canada

5. Department of Basic Science, Biomedical Science Research Lab, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción, Chile

6. Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA

7. Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295, USA

8. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

Abstract

Abstract Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.

Funder

Canadian Institutes of Health Research

Cervical Spine Research Society and the Physicians’ Services Incorporated Foundation

Publisher

Oxford University Press (OUP)

Subject

General Earth and Planetary Sciences,General Environmental Science

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