NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) leads to significant functional impairments below the level of the injury, and astrocytes play a crucial role in the pathophysiology of SCI. Astrocytes undergo changes and form a glial scar after SCI, which has traditionally been viewed as a barrier to axonal regeneration and functional recovery. Astrocytes activate intracellular signaling pathways, including nuclear factor κB (NF-κB) and Janus kinase-signal transducers and activators of transcription (JAK/STAT), in response to external stimuli. NF-κB and STAT3 are transcription factors that play a pivotal role in initiating gene expression related to astrogliosis. The JAK/STAT signaling pathway is essential for managing secondary damage and facilitating recovery processes post-SCI: inflammation, glial scar formation, and astrocyte survival. NF-κB activation in astrocytes leads to the production of pro-inflammatory factors by astrocytes. NF-κB and STAT3 signaling pathways are interconnected: NF-κB activation in astrocytes leads to the release of interleukin-6 (IL-6), which interacts with the IL-6 receptor and initiates STAT3 activation. By modulating astrocyte responses, these pathways offer promising avenues for enhancing recovery outcomes, illustrating the crucial need for further investigation into their mechanisms and therapeutic applications in SCI treatment.

Keywords: JAK/STAT; NF-κB; astrocyte; glial scar; spinal cord injury.

Figure 1

The interaction between the nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways, particularly in response to TNF-α stimulation, involves a complex cascade of events. Activation of NF-κB leads to the transcription of certain genes, including interleukin-6 (IL-6) and leukemia inhibitory factor (LIF). The IL-6 produced by this process can act in an autocrine or paracrine manner, activating its receptor and leading to further signaling events. This activation involves the IL-6R/glycoprotein (gp130) complex and Janus 1/2 (JAK1/2) kinases, which then phosphorylate STAT3. Phosphorylated STAT3 enters the nucleus to initiate transcription of its target genes, including suppressor of cytokine signaling 3 (SOCS3) and cellular inhibitor of apoptosis 2 (cIAP2). This cycle illustrates the intricate crosstalk between these two pathways in cellular signaling.

Figure 2

In response to damage, astrocytes are characterized by the activation of inflammatory pathways, including NF-κB. This leads to increased expression of components like complement component expression (C1r, C1s, C3, and C4), contributing to synaptic damage. They also express inflammatory mediators such as IL-1β, tumour necrosis factor α (TNF-α), and IL-6. These astrocytes exhibit hyperphosphorylation and activation of the STAT pathway, typically in response to injury. Additionally, the inhibition of the anti-inflammatory phosphoinositide 3-kinases (PI3K-Akt) pathway in these cells results in decreased expression of neurotrophic factors, which contributes to synaptic loss and apoptosis.