Interleukin-1 Beta Neutralization Attenuates Traumatic Brain Injury-Induced Microglia Activation and Neuronal Changes in the Globus Pallidus

Abstract

Traumatic brain injury (TBI) increases the risk of delayed neurodegenerative processes, including Parkinson’s disease (PD). Interleukin-1beta (IL-1β), a key pro-inflammatory cytokine, may promote secondary injury development after TBI. Conversely, neutralizing IL-1β was found to improve functional recovery following experimental TBI. However, the mechanisms underlying the behavioral improvements observed by IL-1β neutralization are still poorly understood. The present study investigated the role of IL-1β on the microglia response and neuronal changes in the globus pallidus in response to diffuse TBI. Mice were subjected to sham injury or the central fluid percussion injury (cFPI) (a model of traumatic axonal injury), and were randomly administered an IL-1β neutralizing or a control antibody at 30 min post-injury. The animals were analyzed at 2, 7, or 14 days post-injury. When compared to controls, mice subjected to cFPI TBI had increased microglia activation and dopaminergic innervation in the globus pallidus, and a decreased number of parvalbumin (PV) positive interneurons in the globus pallidus. Neutralization of IL-1β attenuated the microglia activation, prevented the loss of PV+ interneurons and normalized dopaminergic fiber density in the globus pallidus of brain-injured animals. These findings argue for an important role for neuro-inflammation in the PD-like pathology observed in TBI.

Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury

“…In the cortex, the microglia/macrophage response was limited in distribution indicating a more contained inflammatory response. As a result of IL1β involvement in microglia activation and proliferation as well as monocyte recruitment, our observed decreased microglia/macrophage density in the perilesional cortex and CA1 may be a result of CoSyn-mediated reduction in IL1β expression (Basu et al, 2002;Ozen et al, 2020). As the tissue-resident macrophage, microglia are key players in the inflammatory process following brain injury resulting in regenerative, phagocytic, and pro-/anti-inflammatory phenotypes (Xu et al, 2017).…”

“…Interleukin-1-beta (IL1β) is an early inflammatory cytokine that is restored to sham-levels within 1 week following injury and is involved in the secondary injury cascade (Dalgard et al, 2012 ; Lagraoui et al, 2012 ; Taib et al, 2017 ). IL1β neutralization studies demonstrated the causal role of increased IL1β levels in driving neuronal loss (Ozen et al, 2020 ), circulating macrophage recruitment (Basu et al, 2002 ), injury-induced oligodendrocyte damage (Flygt et al, 2018 ), and microglial activation and proliferation following TBI (Ozen et al, 2020 ). Collectively, these data suggest reduced IL1β is beneficial following experimental TBI.…”

Transport study of interleukin-1 inhibitors using a human in vitro model of the blood-brain barrier

“…Levels of IL-1β have been correlated with worsening of infarct severity ( Yamasaki et al., 1995 ), and genetic deletion of IL-1β and IL-1R1 have resulted in positive or neuroprotective outcomes in murine stroke model ( Boutin et al., 2001 ; Lazovic et al., 2005 ). In TBI, untoward effects of IL-1β are supported by preclinical findings ( Clausen et al., 2011 ; Ozen et al., 2020 ). In congruence, administration of rHuIL-1Ra in preclinical TBI models and to patients have shown favourable effects such as reduced neuroinflammation and improved cognition ( Helmy et al., 2014 ; Newell et al., 2018 ).…”

Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits

“…In terms of the complexity of cortico-ponto-cerebellar pathways, one possibility could be the involvement of other brain regions, such as pontine nuclei and basal ganglia converging on different subset of Purkinje cells with altered synaptic input and connectivity patterns in the damaged cerebellum. On the other hand, cFPI also results in striatal pathology, in particular in the globus pallidus, which may also have influenced the beam walk test [ 37 ]. However, while not specific for cerebellar function this test remains sensitive in the assessment of cerebellar pathology [ 28 ].…”