Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation

Abstract

Background: Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key secondary injury factor that can result in further neuronal injury. In the present study, we investigated the role of endogenous MK in secondary injury, including neuroinflammation, immune response, and neuronal apoptosis activity, after TBI. Methods: Wild type (Mdk +/+) and MK gene deficient (Mdk −/−) mice were subjected to fluid percussion injury for TBI models and compared at 3, 7, and 14 days after TBI, in terms of the following: brain tissue loss, neurological deficits, microglia response, astrocytosis, expression of proinflammatory M1 and anti-inflammatory M2 microglia/ macrophage phenotype markers, and apoptotic activity. Results: As opposed to Mdk +/+ mice, Mdk −/− mice reported a significantly reduced area of brain tissue loss and an improvement in their neurological deficits. The ratios of the Iba1-immunoreactive microglia/macrophages in the perilesional site were significantly decreased in Mdk −/− than in the Mdk +/+ mice at 3 days after TBI. However, the ratios of the glial fibrillary acidic protein immunoreactive area were similar between the two groups. The M1 phenotype marker (CD16/32) immunoreactive areas were significantly reduced in Mdk −/− than in the Mdk +/+ mice. Likewise, the mRNA levels of the M1 phenotype markers (TNF-α, CD11b) were significantly decreased in Mdk −/− mice than in Mdk +/+ mice. Furthermore, flow cytometry analysis identified the M2 markers, i.e., CD163 + macrophages cells and arginase-1 + microglia cells, to be significantly higher in Mdk −/− than in Mdk +/+ mice. Finally, the ratios of apoptotic neurons were significantly decreased in the area surrounding the lesion in Mdk −/− than in Mdk +/+ mice following TBI. Conclusion: Our findings suggest that MK-deficiency reduced tissue infiltration of microglia/macrophages and altered their polarization status thereby reducing neuroinflammation, neuronal apoptosis, and tissue loss and improving neurological outcomes after TBI. Therefore, targeting MK to modulate neuroinflammation may represent a potential therapeutic strategy for TBI management.

HMGB1-Mediated Neuroinflammatory Responses in Brain Injuries: Potential Mechanisms and Therapeutic Opportunities

“…Moreover, microglia are well-established as the primary mediators of the innate inflammatory responses in the brain [50]. They have been shown to be rapidly activated at the site of the insult and differentiate either into a detrimental/pro-inflammatory (M1) or a beneficial/anti-inflammatory (M2) phenotype, based on the specific conditions of their host tissue microenvironment [51,52].…”

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

“…The chemoattractant properties of MK for recruitment of peripheral immune cells may explain, in part, the results of a recent study on the examined traumatic brain injury (TBI) in MK KO adult mice (87). Here, MK KO mice had reduced levels of apoptosis at 7 days post-TBI as assessed via cleaved caspase 3 expression and showed improved neurological outcomes at 14 days following TBI.…”

“…A summary of these processes for encephalopathy of prematurity (EoP) and NE linked to HI is given in Table 4 together with a summary of proposed MK approaches. The focus of this review is perinatal brain injury, but it is highly likely that MK would also be useful for targeting damaging processes occurring during adult brain injury, such as stroke or traumatic brain injury (8,87). Injury process do differ by age though, for example, that cell death in the developing brain is more likely to occur via a caspase-dependent process (88) and that microglia are in a "brain building" mode in the developing brain, compared to an adult homeostatic role (89).…”

“…However, in the case of TBI, blood-brain barrier (BBB) permeability is significantly increased with effects seen up to 7 days post injury, facilitating leukocyte trafficking to the brain parenchyma (169). As such, the chemotactic properties of MK may potentiate injury to the adult CNS via amplifying recruitment of peripheral immune cells, and this could explain the reported beneficial effect of MK KO in the adult mouse model of TBI (87). Due to known age-dependent differences in BBB permeability, chemokine function, and leukocyte recruitment following CNS injury (170), it will be important to characterize the effect of MK activity in the context of the developing CNS.…”

Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury

“…This improved functional outcome is achieved through the modulation of both neuroinflammatory responses and neuronal apoptosis surrounding the lesion at the early phase after TBI. Furthermore, MK-deficiency suppressed M1 microglia phenotype marker and promoted M2 phenotype counteracting tissue loss [ 51 ], thus emphasizing that manipulation of genes involved in microglial polarization status may be a potential therapeutic strategy for TBI.…”