Traumatic spinal cord injury (SCI) is a devastating event that results in intractable physical dysfunction, such as paralysis, sensory loss, autonomic dysfunction, urinary disturbance, and central neuropathic pain [1]. The loss of neural circuitry develops in two pathological stages [2]: primary injury refers to the initial mechanical insult to the spinal cord, causing instantaneous disruption of neural components. Soon after, secondary injury cascades occur and persist for several weeks or months, causing additional deterioration of the spared spinal cord tissue surrounding the primary lesion. Mechanisms of the secondary injury cascade include a series of pathological events, such as hemorrhage, ischemia, edema, oxidative stress, ionic imbalance, and neuroinflammation [2,3].

The inflammatory response following SCI plays a critical role in the development of secondary injury. The primary injury triggers the activation of resident immune cells in the spinal cord (i.e., astrocytes and microglia) through various signaling pathways, such as nuclear factor κB (NF-κB), mitogen-activated protein kinases, Janus kinase/signal transducer, and pyrin domain-containing 3/inflammasome pathways [4,5]. Activated immune cells upregulate the expression of pro-inflammatory cytokines/chemokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C–C motif chemokine 2 (CCL2)/monocyte chemoattractant protein 1 [5]. Pro-inflammatory mediators promote the subsequent activation of resident immune cells and infiltration of a wide range of blood-derived immune cells (i.e., neutrophils, monocytes/macrophages, B cells, and T cells) into the lesion site [6]. The activated immune cells interact with each other and form a cascade of inflammatory responses, exacerbating neuronal apoptosis and residual tissue degeneration [3,6]. The severity of the primary injury is predetermined by the intensity of force applied to the spinal cord, yet the neuroinflammation cascade can be minimized by optimal interventions within a therapeutic time window of a few weeks [7].

The transcription factor protein IκBζ (encoded by the Nfkbiz gene) was identified as a new member of the IκB family, and is required for the selective expression of a subset of NF-κB target genes [8]. IκBζ is ubiquitously expressed at low levels in resting cells and rapidly induced in most tissues upon stimulation of IL-1-receptor or Toll-like receptors [9]. Several studies have demonstrated the pro-inflammatory effects of IκBζ on blood immune cells [[10], [11], [12]]. However, the physiological roles of IκBζ are not fully understood since Nfkbiz−/− mice show features of inflammatory diseases such as Sjögren's syndrome and severe atopic dermatitis [13,14]. Here, we hypothesized that IκBζ expressed in blood cells is involved in the development of secondary injury, thereby affecting functional recovery after SCI. The purpose of this study was to investigate the effect of IκBζ deletion in hematopoietic cells using a mouse model of contusion SCI.