Shaping the Responders: How inflammation and environment tune microglial function after spinal cord injury
Year: 2026
Type: dissertation
Abstract: Spinal cord injury (SCI) triggers a complex and prolonged inflammatory response for which no effective immune-regenerative therapy currently exists. Targeting microglial activation has emerged as a promising strategy, as these cells orchestrate both early inflammatory damage and later repair. Interleukin (IL)-13 is a compelling immunotherapeutic candidate, with previous work demonstrating improved recovery when delivered in vivo. However, the conditions that permit IL-13 to modulate microglia effectively, remain poorly defined. This thesis addresses this gap by examining how inflammation, microenvironmental factors, and tissue organisation shape IL-13 responsiveness after SCI. We first reviewed advances in 3D neuroinflammatory systems, outlining how multicellular organisation, ECM composition, and spatial architecture shaped cytokine signalling and establishing the rationale for studying IL-13 within models that more closely reflect CNS structure. We then examined IL-13 signalling in 2-dimensional BV2 and murine induced pluripotent stem cell (miPSC)-derived microglia, where IL-13 induced a STAT6-dependent alternative activation programme under homeostatic conditions. However, this was strongly constrained by lipopolysaccharide (LPS)-driven inflammatory pathways, as well as microenvironmental features relevant to SCI including elevated potassium, excess glutamate, fibronectin, and acidosis. Restoring homeostatic inputs such as TGFbeta, MCSF, and cholesterol improved IL-13 polarising efficacy on microglia, defining the microenvironmental and transcriptional conditions under which IL-13 can engage its regulatory functions. Next, we examined whether pathway-specific inhibition could enhance IL-13 efficacy. TLR4 blockade reinstated IL-13-driven Arg-1 expression and improved microglial morphology under inflammatory challenge, whereas TREM1 inhibition showed stimulus-dependent effects consistent with its role as an amplifier of myeloid activation. Finally, we assessed IL-13 within 3D neuron-astrocyte-microglia containing neurospheroids, revealing that microglia fundamentally reconfigure baseline tissue identity, amplify DAMP responses, and enable IL-13 driven ECM, metabolic, and glycosylation pathways not captured in bipartite (neuron-astrocyte) models. Combined DAMP + IL-13 stimulation induced hybrid transcriptional states, indicating that IL-13 integrates with, rather than simply opposes, injury signalling networks. Looking forward, this thesis establishes a mechanistic framework explaining why IL-13 efficacy varies across SCI models and identifies the environmental, signalling, and structural conditions required to unlock its reparative potential. Thus, providing a foundation for developing context-aware, phase-specific IL-13-based interventions in SCI.
Author: Aiyegbusi, Emmanuelle Damilola
Language: English
Topic: Spinal Cord Injury Research
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7162168644