Faculty Collaboration Database

IL-12p40 promotes secondary damage and functional impairment after spinal cord contusional injury. J Neurosci Res 2022 Dec;100(12):2213-2231

Date

09/13/2022

Pubmed ID

36089917

DOI

10.1002/jnr.25122

Scopus ID

2-s2.0-85137752150 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Secondary damage obstructs functional recovery for individuals who have sustained a spinal cord injury (SCI). Two processes significantly contributing to tissue damage after trauma are spinal cord hemorrhage and inflammation: more specifically, the recruitment and activation of immune cells, frequently driven by pro-inflammatory factors. Cytokines are inflammatory mediators capable of modulating the immune response. While cytokines are necessary to elicit inflammation for proper healing, excessive inflammation can result in destructive processes. The pro-inflammatory cytokines IL-12 and IL-23 are pathogenic in multiple autoimmune diseases. The cytokine subunit IL-12p40 is necessary to form bioactive IL-12 and IL-23. In this study, we examined the relationship between spinal cord hemorrhage and IL-12-related factors, as well as the impact of IL-12p40 (IL-12/IL-23) on secondary damage and functional recovery after SCI. Using in vivo magnetic resonance imaging and protein tissue analyses, we demonstrated a positive correlation between IL-12 and tissue hemorrhage. Receptor and ligand subunits of IL-12 were significantly upregulated after injury and colocalized with astrocytes, demonstrating a myriad of opportunities for IL-12 to induce an inflammatory response. IL-12p40^-/- mice demonstrated significantly improved functional recovery and reduced lesion sizes compared to wild-type mice. Targeted gene array analysis in wild-type and IL-12p40^-/- female mice after SCI revealed an upregulation of genes associated with worsened recovery after SCI. Taken together, our data reveal a pathogenic role of IL-12p40 in the secondary damage after SCI, hindering functional recovery. IL-12p40 (IL-12/IL-23) is thus an enticing neuroinflammatory target for further study as a potential therapeutic target to benefit recovery in acute SCI.

Author List

Rosas Almanza J, Stehlik KE, Page JJ, Xiong SH, Tabor EG, Aperi B, Patel K, Kodali R, Kurpad S, Budde MD, Tarima S, Swartz K, Kroner A

Authors

Matthew Budde PhD Associate Professor in the Neurosurgery department at Medical College of Wisconsin
Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of Wisconsin
Shekar N. Kurpad MD, PhD Chair, Director, Professor in the Neurosurgery department at Medical College of Wisconsin
Karin R. Swartz MD Assistant Dean, Professor in the Neurosurgery department at Medical College of Wisconsin
Sergey S. Tarima PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cytokines
Female
Inflammation
Inflammation Mediators
Interleukin-12 Subunit p40
Ligands
Mice
Recovery of Function
Spinal Cord
Spinal Cord Injuries