Modulation of inflammatory response after spinal cord injury

• Autores: Jesús Amo Aparicio
• Directores de la Tesis: Rubén López Valés (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Dolores Jaraquemada Pérez de Guzmán (presid.), Hugo Peluffo Zavala (secret.), Joan Vidal Samsó (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Autónoma de Barcelona
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • Spinal cord injury (SCI) consists in the disruption of the ascending and/or descending information pathways due to the death of nervous tissue. Since axons from the central nervous system do not regenerate, injury results in a permanent lack of communication between the brain and the regions of the body below the lesion site. This lack of communication translates into loss of movement, loss of sensation, autonomic deficits, and pain. The final magnitude of these dysfunctions is defined by the level, the severity, and the type of injury. However, there are many secondary degenerative processes that take place in the spinal cord after primary injury and contribute to the final dysfunctions. Among these processes, inflammatory response is one of the most important.

    Spinal cord injury elicits an inflammatory response produced mainly by macrophages and microglia. All the process is orchestrated by cytokines. These cells and mediators are fundamental for the clearance of cellular debris and the healing of damaged tissue. However, in contrast to other tissues, inflammatory response in the central nervous system is not properly resolved. Exacerbated and uncontrolled inflammatory response produces damage to healthy neighboring tissue, increasing the lesion size and worsening the final deficits. The main objective of this thesis is the modulation of the inflammatory response after SCI, maintaining the essential benefits of immune response but avoiding dangers of exacerbated immunity. We hypothesize that this modulation will result in improvement of tissue preservation and functional recovery in a murine model of SCI.

    First two strategies of this thesis are based on the suppression of pro-inflammatory environment targeting IL-1α and IL-1β, main cytokines in the first stages of the inflammatory response. Targeting of IL-1α was performed by MABp1, a monoclonal antibody recently approved for clinical use. This antibody neutralizes the soluble form of IL-1α and inhibits its binding to receptors. Besides promising findings in other inflammatory-mediated diseases, MABp1 failed to promote protection after SCI. Targeting of IL-1β was performed by OLT1177, an inhibitor of the NLRP3 inflammasome needed for the processing and release of IL-1β and IL-18. OLT1177 successfully promoted tissue protection and locomotor improvement when injected intraperitoneally after SCI. Since OLT1177 is safe in humans, it is a promising candidate for the treatment of SCI.

    Last two strategies of this thesis are based on the potentiation of the anti-inflammatory environment by IL-37 and IL-13. Previous result from our group showed that increasing IL-37 levels promoted a protective effect after SCI. Here we studied the contribution of the nuclear and extracellular pathways to the role of IL-37. We demonstrated that, although both pathways promote protective effects, benefits after SCI were attributed mainly to extracellular signaling. We also elucidated that IL-37-based therapy only is effective when injected intraspinally. Increasing levels of IL-13 promoted anti-inflammatory environment after SCI, as previously reported by our group with IL-4. However, in contrast to IL-4, IL-13 failed to confer functional improvement. To determine differences between these two cytokines, we performed the first cell-specific RNA sequencing of macrophages and microglia after SCI. We observed that, although both cytokines have the same effect on the modulation of the injury environment, they induce differences in the metabolism of macrophages and microglia. Metabolism induced by IL-4 was more oxidative whereas metabolism induced by IL-13 was more glycolytic. Since inflammatory response is a very demanding process, how cell obtain energy may be crucial for the development of the immune response and may explain differences observed at functional level. Future of SCI is multidisciplinary. Through this thesis we provide evidence to support that trophic modulation of the injury environment is a fundamental component of novel therapeutic approaches to treat SCI.