System failure: Systemic inflammation following spinal cord injury

Abstract

Spinal cord injury (SCI) affects hundreds of thousands of people in the United States, and while some effects of the injury are broadly recognized (deficits to locomotion, fine motor control, and quality of life), the systemic consequences of SCI are less well-known. The spinal cord regulates systemic immunological and visceral functions; this control is often disrupted by the injury, resulting in viscera including the gut, spleen, liver, bone marrow, and kidneys experiencing local tissue inflammation and physiological dysfunction. The extent of pathology depends on the injury level, severity, and time post-injury. In this review, we describe immunological and metabolic consequences of SCI across several organs. Since infection and metabolic disorders are primary reasons for reduced lifespan after SCI, it is imperative that research continues to focus on these deleterious aspects of SCI to improve life span and quality of life for individuals with SCI.

Keywords: Adipose tissue; Bladder; Bone marrow; Gut; Inflammation; Liver; Lungs; Spinal cord injury.

Figure 1.

Sympathetic innervation of organ systems. Spinal cord injury (SCI) results in a loss of descending inhibitory control over the sympathetic nervous system. The organ systems affected by injury-induced sympathetic overdrive depend on the level of injury, with the most common injuries sustained in the lower-cervical levels of the spinal cord. Sympathetic preganglionic neurons arise from the thoracic and upper lumbar regions of the cord before passing through the sympathetic chain and synapsing with postganglionic neurons throughout the body. The effects of SCI vary depending on the organ, ranging from immune dysfunction and loss of resident macrophages to increased inflammation and infiltration of peripheral leukocytes. Together, SCI-induced immune dysfunction forms a complex syndrome of symptoms and complications.

Figure 2.

The lung microenvironment after spinal cord injury (SCI). The lung experiences both increased inflammation and immune dysfunction after SCI. Inflammatory neutrophils traffic to the lung following SCI where they degranulate and release inflammatory mediators, causing tissue damage and diminished lung function. At the same time, sympathetic dysregulation causes a loss in alveolar macrophages and lymphocytes. Some of the decrease in lymphocyte counts can be linked to bone marrow failure syndrome, while the loss in alveolar macrophages increases risk for lung infection. In sum, the lung experiences both acute inflammation and chronic immunosuppression after SCI.

Figure 3.

Spinal cord injury (SCI) causes inflammation and dysfunction within the urinary tract. The urinary tract becomes both inflammatory and more susceptible to infection following SCI. The kidneys undergo glomerulonephritis and an influx of leukocytes from the circulation. These cells release inflammatory mediators such as IL-1β, IL-6, and TNF to propagate and sustain inflammation. As glomeruli necrotize, the kidneys fail to properly clear creatinine which results in excess blood and protein in the urine. Increased sympathetic signaling to the bladder can cause a breakdown of the urothelium and leakage of urine into the bladder wall. This results in leukocyte trafficking and inflammation within the bladder. Sustained sympathetic signaling can also impair detrusor muscle function and prevent incomplete urine voiding, which increases the risk for infection.

Figure 4.

Development of nonalcoholic steatohepatitis after spinal cord injury (SCI). SCI causes a breakdown in the mucosal membrane of the gut and leakage of gut microbiota into circulation. These microbes are carried into the liver via the portal vein and can activate toll-like receptor (TLR) signaling and initiate inflammatory signaling. Adipose tissue is infiltrated by peripheral leukocytes after SCI, resulting in adipocyte apoptosis and lipolysis. The FFAs released into circulation can overwhelm the processing capacity of hepatocytes and contribute to steatosis in the liver. Inflammatory mediators such as TNF and IL-1β result in inflammatory propagation via NF-κB and ceramide synthesis via serine palmitoyl transferase. Ceramides in turn contribute to steatosis and to NF-κB activity. The resulting nonalcoholic steatohepatitis increases the risk of developing cirrhosis and liver cancer.