Targeting CARD6 attenuates spinal cord injury (SCI) in mice through inhibiting apoptosis, inflammation and oxidative stress associated ROS production

Abstract

Spinal cord injury (SCI) causes long-term and severe disability, influencing the quality of life and triggering serious socioeconomic consequences. Lack of effective pharmacotherapies for SCI is largely attributable to an incomplete understanding of its pathogenesis. Caspase recruitment domain family member 6 (CARD6) was initially suggested to be a protein playing significant role in NF-κB activation. However, the effects of CARD6 on SCI progression remain unknown. In this study, the wild type (CARD6+/+), CARD6 knockout (CARD6-/-) and CARD6 transgenic (TG) mice were subjected to a SCI model in vivo, and in vitro experiments were conducted by treating microglia cells with lipopolysaccharide (LPS). Here, we identified CARD6 as a suppressor of SCI in mice. CARD6 knockout significantly accelerated functional deficits, neuron death and glia activation, whereas CARD6 overexpression resulted in the opposite effects. Both in vivo and in vitro SCI models suggested that CARD6 knockout markedly promoted apoptosis by increasing Cyto-c release to cytosol from mitochondria and activating Caspase-3 signaling. In addition, CARD6 knockout mice exhibited stronger inflammatory response after SCI, as evidenced by the significantly elevated expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6, which was largely through enhancing the activation of NF-κB signaling.

Programmed cell death in spinal cord injury pathogenesis and therapy

“…45 Gu et al 46 In another recent study, CARD6, Caspase recruitment domain family member 6, was shown to be a key molecular which could inhibit apoptosis by decreasing Cyto-c release to cytosol from mitochondria and inhibition of Caspase-3 signalling pathway. 50 Zhang et al firstly performed a rat model of SCI, and upregulated p38 was related to inflammation and apoptosis after SCI. Zhang et al also suggested that p38 inhibitor SB203580 treatment could alleviate secondary SCI by suppressing inflammation and apoptosis.…”

Systemic Administration of Fibroblast Growth Factor 21 Improves the Recovery of Spinal Cord Injury (SCI) in Rats and Attenuates SCI-Induced Autophagy

“…Previous studies have shown that SCI can lead to the death of a large number of neurons, the rupture of axons, and the formation of dense glial scar to block axon growth and elongation ( Wang et al, 2019 ; Ma et al, 2020 ; Tran et al, 2020 ). These pathological changes could result in severe motor sensory dysfunction ( Su et al, 2019 ).…”

SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury

“…In general, the primary injury is the result of physical forces including compression, shearing, laceration and acute stretch/distraction that induced by the initial traumatic events, and often determines the injury severity of SCI. The primary injury is followed by a cascade of secondary injury events that characterized by multiple injury processes including in ammation, glutamate excitotoxicity, apoptosis and free radical-induced cell death, and serves to expand the zone of injured neural tissue and exacerbates neurological de cits and outcomes [3]. The in ammatory responses including the activation of resident microglia, recruitment of macrophages, neutrophils and lymphocytes from the bloodstream to the injury site, lead to profound neuropathological consequences such as neuronal death as well as axonal degeneration and demyelination, and the formation of glial scars [4].…”