Systemic inflammation after spinal cord injury: A review of biological evidence, related health risks, and potential therapies

Abstract

Individuals with chronic traumatic spinal cord injury (SCI) develop progressive multi-system health problems that result in clinical illness and disability. Systemic inflammation is associated with many of the common medical complications and acquired diseases that accompany chronic SCI, suggesting that it contributes to a number of comorbid pathological conditions. However, many of the mechanisms that promote persistent systemic inflammation and its consequences remain ill-defined. This review describes the significant biological factors that contribute to systemic inflammation, major organ systems affected, health risks, and the potential treatment strategies. We aim to highlight the need for a better understanding of inflammatory processes, and to establish appropriate strategies to address inflammation in SCI.

Introduction

Traumatic spinal cord injury (SCI) incites an immediate, adaptive inflammatory response characterized by activation of host defense against the tissue damage. Acute inflammation occurs in the spinal cord injury micro-environment at the time of injury, but residual systemic inflammation can continue indefinitely [1] in individuals living with chronic SCI. Chronic SCI is generally defined as ≥ 1-year post-injury, wherein there is stabilization of residual neurological function and a general physiological homeostasis of body composition, hormonal profile, and inflammatory environment [2]. Sensorimotor deficits are an obvious consequences of SCI, however, the spinal cord also plays a critical role in coordinating bodily functions [3] via complex bidirectional communication between the autonomic, endocrine, and immune systems [4,5], which may also be damaged after SCI and result in widespread dysfunction in multiple organ systems [6-8]. For example, with long-term injury, physical limitations related to movement, musculoskeletal activity and weight-bearing contribute to deleterious changes in body composition, including rapid and long-term declines in metabolically active muscle-mass [9-17] and bone [18-24], and significant increases in central adiposity [25-27]. Recurrent and chronic infection in the skin attributable to pressure ulcers [28] and urinary tract infections due to bladder dysfunction and catheter use are common following spinal cord injury [29,30]. These pathophysiological changes are all associated with an inflammatory response [5,6] which appears to promote systemic inflammation in individuals with chronic SCI.

Several recent reviews have previously described chronic systemic inflammation [5,31,32], immune [5] and organ dysfunction [6] associated with SCI. Our focus here is on evidence from human population and epidemiological studies on systemic inflammation in chronic SCI, although we highlight emerging evidence from novel preclinical research. We review the biological factors that contribute to chronic inflammation systemically and in peripheral organs, clinical manifestations, and potential countermeasures to inflammatory-induced pathologies after SCI.

General biomarkers of systemic inflammation

Chronic inflammatory conditions are associated with the prolonged release of inflammatory mediators and the activation of harmful signal–transduction pathways that contribute to aging-related phenotypes and disease development [33] such as cardiovascular disease [34], type II diabetes [35], and many cancers [36]. A multitude of circulating “inflammatory and immune” biomarkers, including cytokines—such as TNF-α, IL-1β, IL-6; acute-phase reactants—such as CRP; chemokines—such as IL-8 and MCP-1; and soluble immune factors, are commonly reported in epidemiologic and intervention studies to be associated with disease risk [37,38]. In severe cases, acute injury, trauma and infection, incite excessive production of cytokines in a so called pro-inflammatory “cytokine storm” [39,40], which are linked to chronic conditions described as “systemic inflammatory response syndrome” and “multi-organ dysfunction syndrome.” In these circumstances, the persistent elevation of cytokines is associated with long-term damaging effects on organ systems and the development of chronic disease [41]. Importantly, it is now well reported that severe acute SCI and an accompanying pro-inflammatory cytokine storm (Figure 1) incites such systemic and multi-organ inflammatory responses [42-46] where the neurological extent and severity of injury are closely associated with more advanced long-term health complications [6,47]. Both preclinical [48] and post-mortem human data [49] indicate that inflammation at the injury site persists into chronic phases of SCI, suggesting it may contribute to systemic inflammation.

Figure 1.

SCI-Induced acute inflammatory response at the injury site. Reactive Glia including astrocytes and microglia, and infiltrating immune cells including lymphocytes, macrophages, neutrophils that penetrate the damaged blood–spinal cord barrier, both release a myriad of pro-inflammatory cytokines and factors into the injury micro-environment resulting in detrimental neurological deficits.

Systemic inflammatory biomarkers and related health complications in chronic SCI

Both case reports and larger cohort studies provide evidence of a heightened pro-inflammatory state with chronic SCI [31,50,51]. In particular, CRP, an established clinical marker of systemic inflammation and cardiovascular disease risk [52,53] is elevated in individuals with chronic SCI [54-59]. A recent pooled-analysis of SCI-specific studies (n = 259), demonstrated that mean CRP levels accompanying SCI exceed high-risk criterion guidelines [51,60] for acute infection or chronic inflammatory diseases (such as cardiovascular disease). Importantly, CRP is considered a predictor of myocardial infarction, peripheral vascular disease, stroke, and sudden cardiac death [61], and as described by Nash et al. [51], CRP integration into global cardiovascular disease risk determination, worsens the hazard ratio for cardiometabolic syndrome in SCI subjects [51]. Another study in subjects with chronic SCI (n = 93), found that higher mean CRP was associated with fasting insulin resistance and severe dyslipidemia [55], both metabolic risk factors for cardiovascular disease.

Associations with several additional pro-inflammatory cytokines have also been reported with chronic SCI. Several studies report elevated levels of TNF-α [62,63], IL-6 [58,64], and IL-2 [62] in subjects with chronic SCI compared to uninjured controls, and with SCI, elevated levels of IL-6 are also positively correlated with vascular cellular adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (IAM-1), indicators of vascular inflammation [58]. Interestingly, a similarly powered study indicated no differences compared to controls with respect to TNF-α and IL-6 [54]. Some studies aim to assess the contribution of infection/skin ulcers, age, level, extent, and duration of injury and other clinical factors to an SCI-related chronic inflammatory state. One recent report has studied this in depth with respect to CRP levels in chronic SCI. Goldstein et al. [65] found that higher CRP was associated with greater BMI, urinary catheter use, recent respiratory illness, and non-white race. They also found that mean CRP increased with decreasing mobility, and overall, these characteristics were more important than the level and completeness of injury. Nonetheless, collectively, CRP, TNF-α, and IL-6 are cytokines most notably reported as pro-atherogenic, and associated with other cardiometabolic risks including insulin resistance, depressed plasma HDL-C, and obesity [66-69], all of which are commonly observed in chronic SCI [51,70-72]. This is important as mortality due to chronical cardiovascular disease has become more common in chronic SCI [73-75]. An additional SCI-specific risk factor in patients with injury at or above the level of sympathetic outflow (T6) [76], is autonomic dysfunction and the clinical manifestation of autonomic dysreflexia, known to exacerbate inflammatory stress [77], potentially accelerating pro-atherogenic processes and cardiovascular disease [75,77,78].

Further epidemiological studies indicate that the chronic inflammatory milieu post-SCI is associated with an array of secondary health risks in many organs and systems including the respiratory, gastrointestinal (GI) and urinary systems. For example, several cross-sectional studies found a significant inverse association between plasma levels of CRP and IL-6 and indices of pulmonary dysfunction that included reduced forced expiratory volume (FEV) and forced vital capacity (FVC) [79,80]. Although the biological role of these cytokines in pulmonary dysfunction have not been directly studied, these observations may again be important, given the aforementioned relationship between cytokines and chronic organ failure, and that pulmonary complications remain among the most common causes of mortality in chronic SCI [73,74,81-83]. In addition, the impact of SCI on the GI system results in several complications of which motility issues and bowel management are most frequently reported [84-86]. More recently, gut dysbiosis has been implicated in SCI-mediated GI pathophysiology, which may be a novel source of inflammation. Bacterial-derived lipopolysaccharides (LPS) induces a low-grade inflammatory state associated with obesity, insulin resistance, diabetes and CVD [87,88], and short-chain fatty acids (SCFA), are known to play an important role in regulating inflammation and insulin resistance [89]. As reviewed by Noller et al. [31] one study in humans with SCI found a decrease in SCFA-producing bacteria which was associated with greater bowel dysfunction compared to controls [90]. Interestingly, there is also an association between asymptomatic bacteriuria and elevated levels of inflammatory and immune biomarkers [91] (although not CRP, TNF-α, or IL-6), and a recent report described differences in the urinary microbiome between subjects with SCI and non-disabled control, and with time since injury in the SCI cohort [92]. Taken together, these studies suggest that microbiome alterations with SCI may contribute to inflammatory stress in the GI and urinary system, although additional research is needed to understand whether changes in the microbiota in these systems are pathological and/or contribute to associated cardiometabolic risks.

One of the most severe consequences of SCI is a profound alteration in body composition typified by rapid and long-term declines in sub-lesional bone and muscle mass, and an increase in adiposity, which has resulted in the prevalence of obesity with chronic SCI [71], and is predictive for cardiometabolic syndrome and CVD [93,94]. Obesity has been identified as the most prevalent cardiometabolic disease component risk accompanying SCI [95], and co-exists with dyslipidemia, glucose intolerance, and insulin resistance [56,96-98], all being comorbidities that are strongly associated with a “pro-inflammatory phenotype” that accelerates atherogenesis and CVD [99,100]. There is increasing scientific evidence implicating “pro-inflammatory” adipose-derived cytokines–adipocytokines—as a principal source of systemic inflammatory factors in both chronic SCI and non-disabled populations [56,58,101-103]. In both SCI and nondisabled individuals meeting the clinical definition of obesity, serum levels of IL-6 were significantly higher than in non-obese individuals [56,104-106], and in SCI and obesity, a positive correlation was reported between IL-6 and fasting insulin levels [58,107]. Another study found that after SCI, the pro-inflammatory adipocytokines Plasminogen activator inhibitor-1 (PAI-1)—which is elevated in obesity and type 2 diabetes mellitus [108-111], and implicated in atherosclerosis [112]—is negatively correlated with both HDL-C (“good cholesterol”) and the anti-inflammatory adipocytokine adiponectin, suggesting PAI-1 may contribute to obesity mediated metabolic complications, albeit conjecture at this point. Additionally, a recent report found an inverse relationship between plasma leptin and reduced pulmonary function in chronic SCI [113], suggesting a link between alterations in body composition and the metabolic syndrome with post SCI-pulmonary function loss.

Inflammatory and immune-mediated pathology in chronic SCI

Inflammation is a component of the immune system response to SCI. Functional crosstalk occurs between the nervous and immune systems via the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenal (HPA) axis [1,114] and lymphoid tissues [115] such as the spleen, thymus, lymph nodes, adrenal gland and bone marrow [5,115,116]. Following SCI, neuro-endocrine and immune system dysfunction result in a “state of immunosuppression” [5,117] including functional deficits in macrophages, natural killer cells, neutrophils, and lymphocytes [4,115,118], having severe consequences such as susceptibility to infection [4,117,119,120]. In fact, as reviewed by Bloom et al. [32], infections are the leading cause of re-hospitalization and of mortality for persons with SCI, who are more than 80 times more likely to die of sepsis than uninjured persons [32]. Importantly, immune cells—most notably macrophages, NK cells, T and B cells—produce and secrete pro-inflammatory cytokines—such as TNF-α and a host of interleukins including IL-1β and IL-6 [121]—in response to infection, injury or trauma [32]. As such, there is both an elevated inflammatory state, and a state of immunosuppression accompanying SCI [5], where deleterious effects of chronic inflammation further exacerbates susceptibility to infection and reduction in wound-healing capabilities [122] by inciting suppressive immune cell phenotypes [32]. Therefore, it is possible that impaired immunity after SCI may contribute to the occurrence of urinary tract infections [62,123], pulmonary infection [124-126], and skin ulcer occurrence and complications [5,127]. Recent neuro-epidemiological studies (n > 1400) demonstrated that post-SCI infections are independent risk factors for poorer recovery, suggesting it is an independent confound for neurobiological rehabilitation [117,128,129], highlighting the complexity and interaction of an ‘uncontrolled’ pro-inflammatory state and immune impairment that accompanies chronic SCI.

Countermeasures to inflammation in chronic SCI

Rehabilitation strategies, or ‘lifestyle’ modifications, such as anti-inflammatory diets and physical activity paradigms have been directly tested in populations with chronic SCI. Several concurrent studies by Allison et al. [130-134] have reported that anti-inflammatory diets are sufficient to reduce several key markers of inflammation including interferon gamma (IFN-γ), TNF-α, IL-1β, and IL-6. Additionally, regular physical activity/training (vs. acute/single session exercise) is understood to have anti-inflammatory effects, particularly under conditions of cardiovascular/cardiometabolic diseases [135], and various exercise paradigms are established strategies to modulate the immune and inflammatory systems in the SCI population [31,136-139]. For example, studies in chronic SCI have demonstrated an inverse relationship between physical activity levels and the cytokines CRP and IL-6 [140,141], and reduced levels of IL-6 with FES cycling [141,142]. Several other population-specific reports found that a long-term arm-crank exercise program reduced systemic levels of TNF-α, IL-6 and the adipocytokine leptin [143], and disparate hand cycling modalities were effective in lowering CRP, IL-6, and CVD risk factors, including waist circumference and insulin resistance [144]. A recent case-series evaluating therapeutic intervention combining diet and exercise paradigms reported successful results in reducing major cardiometabolic risks including insulin resistance [145], albeit very limited in scale and inflammatory data were not reported. More novel approaches to physical activity in SCI include exoskeletal-associated-walking (EAW) [146-149] and home-based exercise programs [150,151], which have included metabolic profiling, although larger studies and more comprehensive results are also needed to directly evaluate their effect on inflammation and cardiometabolic outcomes.

Given their role in chronic inflammation and disease states, several anti-cytokine therapies targeting TNF-α, IL-1β, and IL-6 have been developed and used to treat inflammation in a number of diseases, including rheumatoid arthritis, Crohn’s disease, psoriasis, arthritis and lupus [152,153]. As extensively reviewed by Bloom et al. [32], many anti-inflammatory strategies have focused on acute SCI pathophysiology and neurological outcomes rather than on long-term outcomes. However, a recent study in an in-vivo model of SCI-induced inflammation and cardiovascular disease may help guide future clinical studies. Bigford et al. [154] directly examined the relationship and time-course between inflammatory cytokines and atherosclerotic disease after SCI in a mouse model, and found that SCI significantly increased disease burden, and several cytokines—including TNF-α, IL-1β, and IL-6—were associated with overall disease load [154]. Importantly, they report that NF-κB inhibition via Salsalate (non-acetylated salicylates) —shown to significantly reduce several inflammatory markers including TNFα and IL-6—attenuated overall inflammatory load and significantly reduced disease. These data highlight that SCI directly incites an accelerated trajectory of systemic inflammation and disease and the potential for anti-inflammatory therapy to mitigate pro-inflammatory and proatherogenic consequences of SCI. Although other studies using animal models have examined immunomodulators of inflammation-associated pathways, small molecule agonists/antagonists of inflammatory signals, and intracellular components of inflammatory machinery (Reviewed in the study by Sun et al. [6]), translational studies applied to human SCI have not yet amassed meaningful data. Although statins are used for cardiovascular risk reduction based on risk score and are indicated6 in persons with diabetes regardless of score [155], current guidelines do not include mention of chronic SCI as a chronic inflammatory risk-enhancing condition where early statin use can be considered.

Emerging targets of inflammations in preclinical studies

Previous evidence has shown that individuals with SCI have greater visceral adipose tissue (VAT) cross-sectional area (i.e., indicative of central obesity), associated with maladaptive metabolic profile, and predictive of impaired glucose tolerance, insulin resistance, and dyslipidemia [156,157]. Again, pre-clinical studies may help direct our understanding of underlying biological mechanisms that contribute to inflammation. For example, VAT and pancreas represent bioactive sites of pro-inflammatory processes mediated by macrophage and T cell activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Activation of the NLRP3 inflammasome is now understood as the mechanism of activation and release of the pro-inflammatory cytokines IL-1β and IL-18 [158], principal in the induction of obesity, insulin resistance, and impaired glucose metabolism [159-161]. A large literature has brought attention to inflammasome activation as an acute innate response to trauma in the CNS [162-164] including acute injury to peripheral lung tissue [165]. One report by Bigford et al. [44] examined NRLP3 inflammasome in both VAT and pancreas in a model of chronic SCI, reporting activation of the inflammasome complex, and subsequent activation of cytokines IL-1β and IL-18, suggesting the inflammasome contributes to chronically acquired low-grade inflammation associated with metabolic disorders and component CVD risk. As reviewed by Wang et al. [166] many therapeutics have been developed to target the NLRP3 inflammasome, with potential in the therapeutic treatment of chronic neurological diseases such as Parkinson and Alzheimer disease, as well as atherosclerosis. Further research is necessary to determine if the inflammasome is a viable target in clinical practice.

Conclusion and future perspective

Chronic SCI results in systemic inflammation, immunosuppression, and multiple organ dysfunction which, left unresolved, leads to an exacerbated maladaptive response of body systems [7,167-169], and increased morbidity and mortality due to chronically acquired diseases such as all-cause CVD [74,170] (Figure 2). Understanding relationships between factors associated with systemic inflammation in chronic SCI and between systemic inflammation, immunosuppression, and organ system function will provide insight into pathways of disease and guide new approaches to prevent chronically acquired diseases. Understanding these relationships will also provide insight into the rationale behind novel approaches to prevent illness, morbidity, and mortality in chronic SCI.

Figure 2.

Systemic and peripheral organ inflammation with chronic SCI. SCI results in long-term and unresolved neurological deficits that have chronic pathological consequences on body systems. Concomitant tissue and organ dysfunction can directly contribute to systemic inflammation and/or lead to major clinical health risks. These health risks further contribute to systemic inflammation resulting in a “feed-forward” system of inflammation. Progressive and unresolved health risks lead to the prevalence of chronic diseases. →downstream effect; → contributes to systemic inflammation; -- > hypothesized; VAT = Visceral Adipose Tissue.