Following spinal cord injury, PDE4B drives an acute, local inflammatory response and a chronic, systemic response exacerbated by gut dysbiosis and endotoxemia

Scott A. Myers; Leila Gobejishvili; Sujata Saraswat Ohri; C. Garrett Wilson; Kariena R. Andres; Amberly S. Riegler; Hridgandh Donde; Swati Joshi-Barve; Shirish Barve; Scott R. Whittemore

Neurobiology of Disease (Apr 2019)

Following spinal cord injury, PDE4B drives an acute, local inflammatory response and a chronic, systemic response exacerbated by gut dysbiosis and endotoxemia

Scott A. Myers,
Leila Gobejishvili,
Sujata Saraswat Ohri,
C. Garrett Wilson,
Kariena R. Andres,
Amberly S. Riegler,
Hridgandh Donde,
Swati Joshi-Barve,
Shirish Barve,
Scott R. Whittemore

Affiliations

Scott A. Myers: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
Leila Gobejishvili: Departments of Internal Medicine and Pharmacology and Toxicology, and Alcohol Research Center, University of Louisville, School of Medicine, 505 South Hancock Street, CTR Building, Room 515, Louisville, KY 40202, USA
Sujata Saraswat Ohri: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
C. Garrett Wilson: UAB School of Medicine, University of Alabama at Birmingham, Bevill Biomedical Research Building, Birmingham, AL 35294, USA
Kariena R. Andres: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
Amberly S. Riegler: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
Hridgandh Donde: Departments of Internal Medicine and Pharmacology and Toxicology, and Alcohol Research Center, University of Louisville, School of Medicine, 505 South Hancock Street, CTR Building, Room 515, Louisville, KY 40202, USA
Swati Joshi-Barve: Departments of Internal Medicine and Pharmacology and Toxicology, and Alcohol Research Center, University of Louisville, School of Medicine, 505 South Hancock Street, CTR Building, Room 515, Louisville, KY 40202, USA
Shirish Barve: Departments of Internal Medicine and Pharmacology and Toxicology, and Alcohol Research Center, University of Louisville, School of Medicine, 505 South Hancock Street, CTR Building, Room 515, Louisville, KY 40202, USA; Correspondence to: Shirish Barve, Alcohol Research Center, University of Louisville, School of Medicine, 505 South Hancock Street, CTR Building, Room 515, Louisville, KY 40202, USA.
Scott R. Whittemore: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Department of Anatomical Science & Neurobiology, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA; Correspondence to: Scott R. Whittemore, Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, School of Medicine, MDR 616, 511 South Floyd Street, Louisville, KY 40202, USA.

Journal volume & issue: Vol. 124
pp. 353 – 363

Abstract

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Emerging evidence links changes in the gut microbiome and intestinal barrier function to alterations in CNS function. We examined the role of endotoxin-responsive, cAMP-specific, Pde4 subfamily b (Pde4b) enzyme in gut dysbiosis induced neuro-inflammation and white matter loss following spinal cord injury (SCI). Using a thoracic contusion model in C57Bl/6 wild type female mice, SCI led to significant shifts in the gut bacterial community including an increase in the phylum Proteobacteria, which consists of endotoxin-harboring, gram-negative bacteria. This was accompanied by increased systemic inflammatory marker, soluble CD14, along with markers of the endoplasmic reticulum stress response (ERSR) and inflammation in the SCI epicenter. Deletion of Pde4b reduced epicenter expression of markers for the ERSR and inflammation, at both acute and chronic time points post-SCI. Correspondingly, expression of oligodendrocyte mRNAs increased. Within the injury penumbra, inflammatory protein markers of activated astrocytes (GFAP), macrophage/microglia (CD11b, Iba1), and the proinflammatory mediator Cox2, were decreased in Pde4b−/− mice. The absence of Pde4b improved white matter sparing and recovery of hindlimb locomotion following injury. Importantly, SCI-induced gut dysbiosis, bacterial overgrowth and endotoxemia were also prevented in Pde4b−/− mice. Taken together, these findings indicate that PDE4B plays an important role in the development of acute and chronic inflammatory response and consequent recovery following SCI.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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