Biochemical and Biophysical Research Communications
Deficiency of unc-51 like kinase 1 (Ulk1) protects against mice traumatic brain injury (TBI) by suppression of p38 and JNK pathway
Introduction
Traumatic brain injury (TBI), a major cause of death and disability worldwide, is characterized by a direct injury to the head, resulting in tissue damage [1]. The function of brain is abnormal in patients with TBI, exhibiting neurological dysfunction, which is mainly caused by various pathological processes, such as inflammatory response, apoptosis and autophagy [2,3]. Despite the improved diagnosis and treatment methods, further study is still necessary to reveal the underlying mechanism by which TBI progresses and thus to develop effective therapeutic strategies.
Unc-51 like autophagy activating kinase 1 (Ulk1), as a serine/threonine kinase, plays a key role in autophagy induction, integrating signals from up-streaming sensors and transducing them to the down-streaming autophagy pathway [4]. In several cell lines, Ulk1 knockdown inhibits autophagy [5]. In addition, liver-specific deficiency of Ulk1 alleviates liver injury in animals through reducing autophagy under the regulation of JNK pathway [6]. Ulk1 is of great importance in the initial stages of autophagy and it is possible that genetic variation in this gene may lead to autophagy-mediated control of cellular processes, such as inflammation and apoptosis [7,8]. As reported previously, stress kinase p38 MAPK in microglia senses inflammatory cue LPS, directly activates Ulk1, reliving the autophagic inhibition on the inflammatory machinery, and therefore allowing for a full immune response [9]. Therefore, we hypothesized that Ulk1 might be also involved in TBI progression through regulating various cellular processes. And up until now, the effects of Ulk1 in TBI have not been reported.
In the present study, the wild type (WT) and Ulk1-knockout (KO) mice were employed to explore the role of Ulk1 in TBI development. We first found that Ulk1 was over-expressed in the hippocampus of WT mice. Ulk1-KO mice showed improved cognitive ability after TBI, accompanied with alleviated histological alterations of hippocampus. Ulk1-deletion reduced hippocampus inflammation and apoptosis in TBI mice. Further, the activation of astrocytes and microglial cells stimulated by TBI was also inhibited by Ulk1-KO. Autophagy, triggered by TBI, in hippocampus of mice was diminished in Ulk1-KO mice. The in vitro study using LPS-stimulated primary astrocytes confirmed that Ulk1 deficiency protected mice from TBI through p38/JNK pathway. These results supplied that Ulk1, at least partially, could be considered as an effective candidate for developing novel therapeutic strategies to suppress TBI progression.
Section snippets
Animals and treatment
Adult wild type (WT) male C57/BL6 and Ulk1-knockout (KO) male mice (6–8 weeks old), weighing approximately 20 ± 2 g, were purchased from Laboratory Animal Center of Shandong University (Shandong, China) and Cyagen Biosciences (Guangzhou, China), respectively. Animals were cultured in a pathogen free feeding center under controlled conditions (temperature 25 ± 2 °C and humidity 70 ± 5%) and a 12:12 h light: dark cycle. Mice were randomly divided into four groups (n = 8/group): WT/Sham, WT/TBI,
Ulk1 is highly expressed in hippocampus of mice after TBI and Ulk1-deficiency improves MWM performance in TBI mice
RT-qPCR and western blot analysis showed an evidently increased expression of Ulk1 in hippocampus of WT mice after TBI at D1, D3, D5 and D7 (Fig. 1A). Consistently, LPS treatment stimulated Ulk1 mRNA and protein expressions in a time-dependent manner (Fig. 1B). To further reveal the effects of Ulk1 in TBI, the WT mice and Ulk1-null mice (Ulk1-knockout/KO) mice were used for further research. MWM analysis was performed after TBI. The performance in probe trial of MWM on day 6 was determined
Discussion
Various molecular mechanisms or signaling pathways are involved in TBI, such as oxidative stress, inflammation, neuronal cell apoptosis and autophagy [[1], [2], [3]]. However, it's still not fully demonstrated. Ulk1 is reported to have a vital contribution in regulating autophagy [[4], [5], [6]]. And Ulk1 has been shown to be associated with brain injury; however, its role in TBI has never been elucidated. The present study evaluated the effects of Ulk1 on a mouse model of TBI. The major
References (30)
- et al.
Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species
Free Radic. Biol. Med.
(2015) - et al.
Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377
Free Radic. Biol. Med.
(2015) - et al.
Neurosteroids reduce inflammation after TBI through CD55 induction
Neurosci. Lett.
(2007) - et al.
Hydrogen sulfide attenuates lipopolysaccharide-induced cognitive impairment: a pro-inflammatory pathway in rats
Pharmacol. Biochem. Behav.
(2010) - et al.
Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling
Cell
(2013) - et al.
Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway
Toxicol. Appl. Pharmacol.
(2016) - et al.
Traumatic Brain Injury. Oxford Textbook of Neurocritical Care
(2016) - et al.
Neuroprotective effects of pifithrin-α against traumatic brain injury in the striatum through suppression of neuroinflammation, oxidative stress, autophagy, and apoptosis
Sci. Rep.
(2018) - et al.
Autophagy in acute brain injury
Nat. Rev. Neurosci.
(2016) J. AMPK→ uLK1→ autophagy
Mol. Cell Biol.
(2011)
The association of AMPK with ULK1 regulates autophagy
PLoS One
ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression
Protein & cell
Association analysis of ULK1 with Crohn's Disease in a New Zealand population
Gastroenterol. res. prac.
p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1
J. Cell Biol.
Mice lacking glutamate carboxypeptidase II develop normally, but are less susceptible to traumatic brain injury
J. Neurochem.
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