Abstract
Traumatic brain injury has a poorer prognosis in elderly patients, possibly because of the enhanced inflammatory response characteristic of advanced age, known as “inflammaging.” Recently, reduced activation of the TANK-Binding-Kinase 1 (Tbk1) pathway has been linked to age-associated neurodegeneration and neuroinflammation. Here we investigated how the blockade of Tbk1 and of the closely related IKK-ε by the small molecule Amlexanox could modify the microglial and immune response to cortical stab-wound injury in mice. We demonstrated that Tbk1/IKK-ε inhibition resulted in a massive expansion of microglial cells characterized by the TMEM119+/CD11c+ phenotype, expressing high levels of CD68 and CD317, and with the upregulation of Cst7a, Prgn and Ccl4 and the decrease in the expression levels of Tmem119 itself and P2yr12, thus a profile close to Disease-Associated Microglia (DAM, a subset of reactive microglia abundant in Alzheimer’s Disease and other neurodegenerative conditions). Furthermore, Tbk1/IKK-ε inhibition increased the infiltration of CD3+ lymphocytes, CD169+ macrophages and CD11c+/CD169+ cells. The enhanced immune response was associated with increased expression of Il-33, Ifn-g, Il-17, and Il-19. This upsurge in the response to the stab wound was associated with the expanded astroglial scars and increased deposition of chondroitin-sulfate proteoglycans at 7 days post injury. Thus, Tbk1/IKK-ε blockade results in a massive expansion of microglial cells with a phenotype resembling DAM and with the substantial enhancement of neuroinflammatory responses. In this context, the induction of DAM is associated with a detrimental outcome such as larger injury-related glial scars. Thus, the Tbk1/IKK-ε pathway is critical to repress neuroinflammation upon stab-wound injury and Tbk1/IKK-ε inhibitors may provide an innovative approach to investigate the consequences of DAM induction.
Highlights
Traumatic Brain Injury (TBI) is a major worldwide cause of morbidity and mortality (Bruns and Hauser, 2003; Jiang et al, 2019)
We considered the total levels of Stimulator of Interferon Genes (STING) protein and of STING phosphorylated on Ser366, a site targeted by TANK-Binding-Kinase 1 (Tbk1) (Liu et al, 2015). pSTING (S366) showed a trend toward reduced levels in AMX treated mice (Figures 1A,B)
Total levels of STING were substantially increased by the AMX treatment, in agreement with the role of Tbk1 in stimulating STING degradation (Prabakaran et al, 2018)
Summary
Traumatic Brain Injury (TBI) is a major worldwide cause of morbidity and mortality (Bruns and Hauser, 2003; Jiang et al, 2019). Irrespective of subpopulation phenotypes, microglia from aging brains secretes higher levels of IL-6 and IL1b (Rawji et al, 2016), expresses a higher level of Toll Like Receptor (TLR) and Major Histocompatibility Complex (MHC) proteins (Letiembre et al, 2009), but display reduced motility and impaired phagocytic capacity (Koellhoffer et al, 2017; Gabandé-Rodríguez et al, 2020) In line with these findings, older mice display a more abundant microglial proliferation and peripheral leukocytes infiltration (in particular neutrophils) upon TBI, larger production of reactive oxygen species, and higher levels of TNF-alpha secretion (Ritzel et al, 2019)
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