Abstract
Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib treatment (6 mg/kg/day, IP, starting 3 h post-injury for 7 or 14 days) reduced BTK activation and total BTK levels, attenuated the injury-induced elevations in Iba1, GFAP, CD138, and IgG at 7 or 14 days post-injury without reduction in CD45RA B cells, improved locomotor function (BBB scores), and resulted in a significant reduction in lesion volume and significant improvement in tissue-sparing 11 weeks post-injury. These results indicate that Ibrutinib exhibits neuroprotective effects by blocking excessive neuroimmune responses through BTK-mediated microglia/astroglial activation and B cell/antibody response in rat models of SCI. These data identify BTK as a potential therapeutic target for SCI.
Highlights
Traumatic spinal cord injury (SCI) impacts motor, bowel, bladder, and sexual function, resulting in a tremendous socioeconomic impact on affected individuals and the health care system [1,2]
B cells play a central role in the adaptive immune system and autoimmunity, while microglia, macrophages, and astrocytes are key mediators of the innate immune system and inflammatory response
Bruton tyrosine kinase (BTK) was originally identified as the gene mutated in X-linked agammaglobulinemia (XLA) and was subsequently shown to be the rate-limiting step in B cell receptor signaling and B cell survival and differentiation [41,42]
Summary
Traumatic spinal cord injury (SCI) impacts motor, bowel, bladder, and sexual function, resulting in a tremendous socioeconomic impact on affected individuals and the health care system [1,2]. Current treatments for acute SCI are largely limited to stabilizing the spine and providing palliative care. Over the past two decades, it has become evident that SCI elicits multicellular and sequential acute inflammatory and delayed autoimmune responses which include activation of microglia, macrophages, and astrocytes, along with B lymphocytes [5–11]. B cells play a central role in the adaptive immune system and autoimmunity, while microglia, macrophages, and astrocytes are key mediators of the innate immune system and inflammatory response. The inflammatory and immune systems can be neuroprotective and growth promoting, their excessive activation shifts the pendulum towards pathology and contributes to neurodegeneration and resultant functional deficits following SCI
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