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.

Introduction

Spinal cord injury (SCI) typically results from trauma or falls, and can strike people of all ages and backgrounds. SCI is commonly viewed as a problem of motor control and sensory loss, resulting in at least partial paralysis. However, those with lived SCI experience have called for more attention into major concurrent issues, such as the increased risk of infections, bladder dysfunction, and predisposition to obesity, diabetes, and liver disease [1]. This review highlights work showing that SCI drives systemic immune dysregulation across the body, negatively impacting major organ systems and general homeostatic mechanisms such as metabolic function and hematopoiesis.

The immune response to injury within the spinal cord itself is well characterized. Primary mechanical damage triggers a secondary cellular response largely orchestrated by resident CNS microglia [2–4]. Beyond promoting repair by clearing cellular and myelin debris after injury, microglia begin a signaling cascade that recruits monocyte-derived macrophages and contributes to subsequent scar formation around the lesion [3, 5–7, 8, 9]. The glial scar largely consists of astrocytes and serves to wall off the hemorrhagic lesion from spared tissue. NG2+ glia also interdigitate within the glial scar and regulate the density of the astrocytic border [10]. Within the lesion core, fibroblasts are recruited with pericytes and extracellular matrix proteins to form a dense fibrotic scar in mice [11–14]. The glial and fibrotic scars are recognized to have dual roles after SCI; on one hand they prevent lesion spread and additional neural degeneration, but they are also thought to reduce long-term axon regrowth [15, 16].

In addition to triggering long-lasting intraspinal inflammation, SCI causes systemic immune dysregulation throughout the body. This is because organs innervated below the injury lose regulatory feedback from the sympathetic nervous system (SNS). More specifically, SCI results in the loss of descending inhibitory control from the brain on preganglionic sympathetic neurons below the lesion, leading to dysregulated and enhanced efferent signaling which modulates immune system throughout the body [17, 18]. For instance, as outlined in Fig. 1, the lungs are partially innervated by sympathetic nerves originating at thoracic levels T1–T4 [19]. Nerves from T5–T9 synapse on post-ganglionic neurons within the celiac ganglion, which then project to the liver, gallbladder, stomach, pancreas, spleen, and duodenum. The kidneys and adrenal glands are innervated between T10–T12 via the aorticorenal ganglion. Nerves emerging between lumbar levels L1 and L2 synapse within the superior mesenteric ganglion to innervate the large and remaining small intestine, whereas L2 fibers passing through the inferior mesenteric ganglion innervate the descending and sigmoid colon, rectum, bladder, and reproductive organs. Parasympathetic control of these organs mostly derives from the vagus nerve, but parasympathetic input to the distal colon and bladder originates in the sacral spinal cord. Nearly all SCI result in some loss of autonomic control below the level of injury. Since cervical injuries occur most frequently, the potential for all these organs to be affected is high. This permanent autonomic dysregulation causes systemic immune and metabolic dysfunction.

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.

The effects of SCI on systemic immunity and inflammation

Spinal trauma can result in SCI-induced immune deficiency syndrome (SCI-IDS), which is characterized by lasting impairment of innate and adaptive immunity. SCI-IDS results from complete or partial disconnection of supraspinal control over immune organs [20, 21]. This increases susceptibility to pathogens and, consequently, the SCI population experiences more infections compared with the general public [22].

Infections in the first year after SCI are an independent risk factor for reduced motor function, illustrating the important interaction between infections and recovery [23]. Further, seemingly minor infections can lead to severe and lethal outcomes; consequently, those with SCI are more likely to die from preventable infections relative to noninjured individuals. Our own work has focused on several aspects of aberrant post-SCI immune regulation, including within the bone marrow, lung, gut, liver, and bladder [24–28]. However, much more work is needed to understand and reverse the overall impaired immune function after SCI.

Paradoxically, while SCI causes SCI-IDS, it also results in local tissue inflammation. Here we will highlight post-SCI inflammation and immune deficiency in a tissue-specific manner. For a more detailed discussion on this overall immune system paradox, the reader is referred to the in-depth review published by Schwab et al. [29].

Bone marrow and spleen

Bone marrow is the primary generative lymphoid organ and is responsible for producing almost all immune cells in the body. Therefore, normal bone marrow function is paramount for fighting infection. Recent data in preclinical models show that SCI causes acquired “bone marrow failure syndrome”, defined by immune cell precursors in the bone marrow undergoing excessive proliferation but failure to mobilize to the blood to fight infection [24]. Features of bone marrow failure syndrome also occur in humans and persist indefinitely [21, 30, 31].

Secondary lymphoid organs are also impacted by SCI, which exacerbates negative infectious outcomes. For instance, the function of the spleen, a major reservoir for adaptive immune cells including B and T lymphocytes, is adversely affected by SCI. SCI causes both acute and prolonged splenic atrophy due at least in part to lymphocyte apoptosis [32]. For cells that do survive, their functions are impaired. For example, immunizations in SCI animals fail to elicit high-titer, antigen-specific antibody responses indicating that T- and B-lymphocyte interactions are inefficient after SCI [33, 34]. Evidence suggests that excess intrasplenic norepinephrine and glucocorticoids after SCI promote lymphocyte death [33]. Indeed, pharmacological blockade of these hormones prevents lymphopenia, offering hope to improve the immune system’s infection fighting ability after SCI.

The lungs

Pulmonary complications such as impaired breathing and infection (e.g. pneumonia) after SCI are well-documented and have detrimental effects on recovery, mortality, and morbidity [23, 35–38]. While paralysis of the respiratory muscles contributes to these complications, especially in individuals who suffer cervical SCI, impairments in tissue-resident pulmonary immunity also play a role. Unfortunately, interventions to alleviate one pulmonary complication frequently exacerbate another. For instance, mechanical ventilation, often necessary to alleviate labored breathing, can cause ventilator-induced lung injury, and evidence suggests that this phenomenon is worsened in individuals with SCI [39–41]. One study found that mechanical ventilation in rats with SCI had exacerbated pulmonary inflammation characterized by pulmonary neutrophilia, indices of epithelial damage, increased inflammatory cytokines, and increased oxidative stress [40]. Further, ventilation-induced damage to the lung fed back to exacerbate intraspinal inflammation in rats [41], demonstrating that pathology in peripheral organ systems can negatively impact spinal cord after injury.

Postinjury changes in pulmonary immunity also occur independent of ventilation. For instance, evidence suggests an injury-driven pulmonary paradox where both pulmonary inflammation and immunosuppression occur after SCI. Regarding pulmonary inflammation, studies show that lung inflammation is linked to systemic inflammation in the systemic inflammatory response syndrome, especially in lower-level incomplete injuries [42–44]. Systemic inflammatory response syndrome is an acute phenomenon occurring after CNS injury when circulating inflammatory cells, particularly neutrophils, invade uninjured peripheral organs including the liver, lung, and kidney. This cellular influx causes tissue damage and multiorgan system failure [42–44].

However, as stated above, systemic immunosuppression also occurs after SCI, including in the lung, especially after high-level complete injuries [20, 27, 33, 34, 45, 46]. In this situation, acute loss of pulmonary lymphocytes is accompanied by reduced alveolar macrophages and impaired immune signaling [27]. Importantly, immune suppression in the lung likely accounts for the increased risk of pulmonary infection after SCI [27]. This increased risk of pulmonary infection can also have a direct impact on motor recovery, as previous clinical work shows that an acute pulmonary infection can impair recovery up to 5 years later, again emphasizing the potential impact of systemic pathology on CNS outcomes after SCI [23].

Concomitant acute neutrophilia and lymphopenia detected in preclinical models also reflects patient data. An examination of blood leukocytes in SCI patients found that at 0–1 dpi SCI patients had elevated blood neutrophils, and that by 1–3 dpi there was an observed decrease in blood lymphocytes [47]. These blood leukocyte changes are associated with motor outcomes and pulmonary infections: acute neutrophilia correlates with impaired motor recovery while an increase in the neutrophil/lymphocyte ratio increases risk of pulmonary infection [47]. While one might predict that elevated neutrophils would prevent acute infection, it appears as though the combination of neutrophilia and lymphopenia drives infection. The mechanisms responsible for the changes in the levels of these two leukocyte populations after SCI or how their interactions change in response to injury are still unknown, and understanding this paradox will be critical for preventing pulmonary infection after SCI. In summary, current research suggests that pulmonary immune dysfunction after SCI, characterized by enhanced tissue-specific inflammation and immunosuppression (Fig. 2), plays important roles in recovery by increasing infection risk and exacerbating CNS-driven impairments in motor function.

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.

Urinary tract, bladder, and kidney

Urinary tract infections (UTI) are some of the most common and troublesome complications following SCI [48]. Indeed, one study following SCI subjects over time showed 100% of subjects developed >1 UTI on average per year over a 40-year span after injury [49]. These infections arise from various sources including kidney failure, problems with bladder voiding, introduction of bacteria by catheterization, and inflammatory cell trafficking and cytokine release in the bladder, kidneys, and urinary tract [48, 50]. Each primary tissue experiences inflammation and infection uniquely, and thus merit discussion in this review (Fig. 3).

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.

Those with SCI remain permanently at risk for renal deterioration, necessitating consistent follow-up examinations [51]. Since the kidneys are principally innervated by efferent fibers arising from spinal cord levels T8 to L1, differences in renal inflammation vary as a function of injury level but are likely present in the majority of injured individuals [52]. Renal deterioration results in reduced creatinine clearance and proteinuria (increased protein in the urine), both of which are associated with increased mortality after SCI [53]. Proteinuria is caused by chronic kidney disease and loss of glomerular function [54, 55]. This loss of function is associated with inflammatory signaling in the kidney, known as glomerulonephritis, at acute and chronic times following SCI [44, 56]. Indeed, inflammatory cytokines such as TNF, IL-1β, and IL-6 rise in the kidney following SCI [56] and are associated with renal infiltration of monocytes, granulocytes, and lymphocytes [43, 44, 57]. Immune cells and cytokines in the kidney directly impact the filtration functions of glomeruli and contribute to increased mortality following SCI. Therefore, it is crucial to better understand and examine the renal inflammatory response to SCI.

In addition to renal complications, SCI typically leads to neurogenic bladder, or the loss of bladder control [58]. Bladder dysfunction occurs rapidly after SCI and is accompanied by significant urothelial disruption, reduced tight junction proteins, and increased permeability of the bladder wall to water and urea within hours of injury [59, 60]. These changes in urothelial structure and function persist chronically in individuals with SCI [61]. Since the bladder is innervated by spinal autonomic neurons primarily at the L1–L2 spinal levels, virtually all SCI will lead to bladder dysfunction [62]. Indeed, SCI patients with cervical and thoracic SCI were shown to have comparable chronic bladder pathology and to be similarly plagued by recurrent UTIs [61, 63].

As a result of postinjury changes, inflammatory mediators are present in bladder walls from acute to chronic stages. Indeed, urothelial biopsies from chronic SCI subjects had elevated levels of inflammatory mediators and apoptotic cells [63]. Despite these inflammatory mediators, postinjury UTI risk remains permanently high for several reasons. First, incomplete voiding of urine increases risk for infection [64], along with increasing the risk for more immediate and serious complications such as autonomic dysreflexia [65, 66]. Long-term catheterization adds additional risks for infection and can directly introduce bacteria into the urinary tract [67, 68]. Further, dysregulated neurogenic control and frank disruption of the urothelium and urothelial tight junctions facilitate bacterial binding to the bladder wall and increased leukocyte infiltration [69]. Inflammatory signals associated with these immune cells exacerbate disruption of the bladder epithelium [60, 70]. However, the inflammatory response to UTI was shown to be muted in rodents with SCI, which, if translated to human SCI, could contribute to the risk for recurrent UTI in the SCI population [71]. Notably, the precise inflammatory mechanisms underlying increased UTI risk after SCI have not been elucidated. Bladder dysfunction and UTI significantly reduce quality of life in the SCI population, and thus more research is required to fully assess bladder and urinary tract inflammation and its effects on bladder function.

Gut dysbiosis

The SNS regulates motility, mucosal secretions (e.g. mucin, acids), vasodilation, and epithelial permeability in the gastrointestinal (GI) tract. Sympathetic preganglionic neurons controlling the small and large intestines are located primarily in the spinal cord segments T5-L2 [72–74]. Therefore, an injury to the spinal cord at almost any level will adversely affect autonomic control of the gut to some degree. The SNS also heavily innervates the gut-associated lymph tissues (GALT), including mesenteric lymph nodes and Peyer’s patches, thereby directly affecting immune function.

After SCI, intestinal inflammation is evident in the GALT and throughout the intestines [26, 75–78]. In SCI mice, elevated cytokine production (TNF, IL-1β, TGF-β1, IL-10) and compositional changes in leukocytes in the Peyer’s patches and mesenteric lymph nodes are evident for at least 1-month postinjury [26]. Similarly, at 8 weeks post-SCI in rats, inflammatory cytokines (IL-12, MIP-2, IL-1β) were increased in the intestines and correlated with the relative abundance of distinct species of gut bacteria [77].

Delayed intestinal transit occurs after SCI and likely contributes to gut inflammation [79]. High thoracic SCI markedly reduces colonic contractions and duodenal blood flow concomitant with reduced mucosal crypt depth, blunted intestinal villi, and elevated inflammatory markers (ICAM-1, CCL2, CCL3) [75, 78]. SCI increases collagen in the colon, which is associated with inflammatory colitis and diminished colonic compliance [78]. Intestinal barrier permeability also rises after SCI, which increases risk for systemic inflammation and can negatively affect locomotor recovery [26, 80, 81].

In addition to altering structural and cellular composition within the intestines and GALT, elevated SNS activity impacts the enteric microbiota. In the neurogenic bowel (i.e. a functionally impaired bowel due to nerve injury), impaired intestinal transit caused by increased SNS activity limits the delivery of necessary nutrients to microbiota in the distal colon. Likewise, hyperreflexive SNS activation impairs mucin production which hinders production of the mucus layer, an important niche and barrier colonized by enteric microbiota. Loss of the mucin barrier increases interactions between gut bacteria and gut epithelia, eventually causing infection, inflammation, and gut dysbiosis. Finally, catecholamines released by SNS activation directly alter the growth rate, virulence factor production, and adherence of various types of gut microbiota in vitro [82–85]. Indeed, the post-SCI inflammatory changes in the GI tract are accompanied by long-lasting changes in the gut microbiome leading to gut dysbiosis [26, 76, 77, 86, 87]. After SCI, fecal microbiota transplants or treatments that increase levels of beneficial gut bacteria are associated with reduced inflammation and lower intestinal permeability, suggesting that these processes are tightly linked with gut dysbiosis [88, 89]. Taken together, gut inflammation after SCI likely results from altered SNS input to gut, immune dysfunction in the GALT, and gut dysbiosis, which together significantly compromise GI function.

The effects of SCI on metabolic function

A separate but related consequence of SCI is dysregulation of metabolism. This issue manifests in every level of metabolic function, from system-wide metabolic dysfunction to the organ level and down to subcellular mitochondrial function [90]. The liver is a major metabolic organ that exhibits chronic pathology after SCI. We previously published a detailed review of this phenomenon [91], but the topic is revisited here in the context of systemic inflammation. It is particularly crucial to understand the link between adipose tissue and the liver after SCI (Fig. 4), as dysregulated lipid metabolism contributes a host of disorders that can be classified as metabolic syndrome (MetS), a leading cause of death and driver of healthcare costs in the SCI population.

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.

Liver

In the liver, MetS manifests as nonalcoholic steatohepatitis (NASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease, the nomenclature of which was recently changed from nonalcoholic fatty liver disease [92, 93]. NASH is characterized by lipid accumulation, inflammation, and cell damage. NASH is typically associated with diet-induced obesity in able-bodied individuals, but NASH has been observed acutely in lean post-SCI rodents. Indeed, mid-thoracic SCI in rats causes rapid hepatic cytokine expression, lipid droplet accumulation, iron sequestration, and overt liver damage [28, 91, 94]. Post-SCI liver pathology is likely driven in part by dysregulation of SNS signaling to the liver. Clinical studies showed episodic increases in serum norepinephrine in SCI subjects, suggesting repeated outbursts of SNS outflow [95]. Notably, norepinephrine causes a 4-7-fold induction of TNF expression by Kupffer cells, the resident hepatic macrophages, revealing the pro-inflammatory nature of excess SNS signaling to the liver [96, 97].

TNF plays a central role in NASH development due to its ability to both propagate inflammatory signaling via NF-κB and initiate ceramide synthesis through increased serine palmitoyl transferase production [98, 99]. Notably, our prior work confirmed rapid induction of hepatic ceramide synthesis after SCI in rats [28]. Ceramides, a waxy lipid species, can increase TNF synthesis by activating TLR-4 [100], thereby perpetuating a deleterious cycle. Ceramides released systemically can cross the blood–brain barrier to induce CNS toxicity and protein aggregation in diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases [101].

Liver inflammation can also be driven by gut dysbiosis, increased gut permeability, and the transportation of microbes from the gut to the liver via the portal vein [102, 103]. Our prior work showed both sustained endotoxemia and bacteria directly populating the liver after SCI [25, 26] and, using metagenomics, showed drastic alterations in the gut virome and microbiome [104]. Gut dysbiosis has also been detected in the SCI population [86, 105, 106]. Since gut microbes entering the liver can activate TLR-4 and potentiate liver inflammation and damage, this is an important target for research to identify therapeutic treatments to prevent SCI-induced liver damage [107, 108].

Not only does SCI induce liver pathology, but liver inflammation can feed back to exacerbate intraspinal inflammation and pathology. For instance, depleting Kupffer cells prior to SCI reduced neutrophil trafficking to the injured cord, while increasing hepatic NF-κB signaling before SCI increased acute neutrophil translocation to the CNS [109]. This central role for Kupffer cells is likely mediated by their capacity to produce growth factors, cytokines, and chemokines, notably TGF-β1, TNF, IL-1β, IL-6, IL-10, IL-18, CXCL2, CCL2, ROS, and prostaglandins. All of these signals stimulate monocytes and neutrophils to enter the inflamed liver and enhance the acute systemic inflammatory response [42, 110].

Our work recently showed that if the liver is inflamed at the time of SCI, not only is acute inflammation enhanced, chronic metabolic pathology is worse, intraspinal tissue lesions are larger, and locomotor recovery is impaired [25]. Thus, the status of liver inflammation at the time of SCI is a disease-modifying factor that can regulate the ultimate level of recovery. Notably, the importance of liver status in humans was recently shown to be valid in a clinical study, where SCI patients with pre-existing liver (or kidney) pathology had increased in-hospital mortality rates [111].

Chronic hepatic pathology translates to a four-fold increased risk for developing cirrhosis and a seven-fold increased risk for hepatic carcinoma after SCI [112]. Further, liver inflammation is related to systemic insulin resistance, renal disease, and has recently been recognized as an independent risk factor for cardiovascular disease [113], all conditions occurring at higher incidence and increased severity in the SCI population [114–116]. Thus, understanding drivers and consequences of liver inflammation and pathology is crucial for restoring homeostasis, metabolic health, and overall recovery after SCI.

Adipose tissue

Clinical studies indicate that over two-thirds of individuals living with SCI are considered obese, as defined by the World Health Organization [117–119]. Adipose tissue mass increases after SCI in the absence of overt obesity, with visceral adipose tissue mass in SCI adults being up to 58% greater than in able-bodied individuals, even after controlling for body weight and caloric intake [120–122]. This again illustrates the high risk for MetS in SCI individuals [122–125].

Classically, adipose tissue was thought to be an inert energy storage depot. However, recent studies show adipose tissue is a potent endocrine organ which secretes numerous hormones and adipokines [126]. Visceral white adipose tissue (WAT) becomes inflamed as adipose accumulates, and increased adiposity induces a chronic, low-grade inflammatory state [121, 127]. In obese WAT, infiltrating macrophages form “crown-like structures” surrounding enlarged, dying adipocytes [128]. Elevated TNF after SCI can suppress WAT insulin receptor signaling, leading to insulin resistance and release of circulating free fatty acids via lipolysis [96, 129, 130].

Though elevated TNF is central to developing cardiometabolic disease and systemic inflammation, other adipokines may contribute to SCI-induced metabolic dysfunction. For instance, IL-1β is increased in subcutaneous and visceral WAT and serum of obese individuals with MetS [131, 132], a finding which was replicated in mouse visceral WAT after mid-thoracic contusion SCI [133].

Similar to other organs, WAT pathology may occur in part from enhanced SNS signaling after SCI. It is known that SCI increases norepinephrine and WAT lipolysis below the lesion level [122], and SNS input is necessary for leptin-stimulated lipolysis in WAT [134]. Dysregulated SNS activation after SCI due to loss of descending control from the brainstem could thus drive aberrant WAT lipolysis [135]. Additionally, activation of α2-adrenergic receptors stimulates TNF production by macrophages and can further contribute to insulin resistance and NF-κB activation [136]. To reduce cardiometabolic risk and improve overall health in the SCI population, future studies are needed to understand the role of adipose tissue inflammation in post-SCI MetS development.

Conclusion

SCI shortens lifespan, which is due, at least in part, to systemic inflammation and MetS-related pathology [137]. Thus, postinjury MetS and inflammation in general remain crucial topics of research. The complexity of each organ’s response to SCI provides compelling targets for future studies, but a systems-based approach is required to address the various nuances and differences between tissues. For example, the paradoxical immunosuppression paired with neutrophilia in the post-SCI lung demonstrates why broad immune modulation will prove difficult in achieving positive results. Given the varying issues presented in this manuscript, we propose that a true solution to SCI-induced dysfunction, both in the spinal cord and in peripheral systems, will require holistic knowledge and flexible, tissue-specific approaches.

Abbreviations:

GALT

gut-associated lymph tissues

GI

gastrointestinal

MASLD

metabolic dysfunction-associated steatotic liver disease

MetS

metabolic syndrome

NASH

nonalcoholic steatohepatitis

SCI

spinal cord injury

SCI-IDS

SCI-induced immune deficiency syndrome

UTI

urinary tract infections

WAT

white adipose tissue

Data availability statement:

Data sharing is not applicable as no new data were generated for this study.