The central nervous system (CNS) regulates inflammation in response to injury by integrating sensory and motor information to generate a coordinated response. The CNS is not an immune-privileged organ; it receives information about injury-induced inflammation through soluble mediators and direct neural projections. Inflammation is sensed via multiple routes, including DAMPs and inflammatory molecules reaching the brain through the fenestrated endothelium of circumventricular organs (CVO) or a leaky blood-brain barrier following TBI. Inflammatory stimuli also interact with brain endothelial cell receptors to generate proinflammatory mediators that impact the brain parenchyma, a response countered by the HPA axis and systemic glucocorticoids. These stimuli cause behavioral changes such as sleep, lethargy, reduced appetite, and fever.

Information regarding tissue damage is also signaled via afferent neural fibers, particularly the vagus nerve. Afferent vagal impulses modulate the brain stem, leading to an "inflammatory reflex" where efferent signals regulate peripheral inflammation. Experimental models show that vagal stimulation reduces proinflammatory cytokine production in the spleen. This process involves vagal efferent fibers synapsing on catecholaminergic splenic nerves, which release norepinephrine to activate β2-adrenergic receptors on acetylcholine (ACh)-producing T cells. The released ACh then targets α-7 nicotinic ACh receptors on splenic macrophages, blocking their activation, inhibiting cytokine production (such as NF-κB translocation), and shifting them toward an M2 anti-inflammatory phenotype.

Traumatic injury triggers a neuroendocrine response to enhance immune defense and mobilize energy. The two primary pathways are the HPA axis (releasing glucocorticoids) and the sympathetic nervous system (releasing catecholamines like epinephrine and norepinephrine). Other hormones involved include growth hormone (GH), macrophage inhibitory factor (MIF), aldosterone, and insulin. The HPA axis is activated when the hypothalamus secretes corticotropin-releasing hormone (CRH), a process mediated by circulating cytokines (TNF-α, IL-1β, IL-6) and afferent vagal fibers. CRH stimulates the anterior pituitary to release adrenocorticotropin hormone (ACTH), which then acts on the adrenal glands to secrete cortisol. Cortisol is the major glucocorticoid in humans and is essential for survival during stress, eliciting anti-inflammatory actions by binding to the glucocorticoid receptor (GR). The activated GR complex can sequester proinflammatory transcription factors like NF-κB in the cytoplasm or promote the transcription of anti-inflammatory genes like interleukin-10.

Adrenal insufficiency in clinical settings often manifests as inadequate cortisol and aldosterone, leading to symptoms like tachycardia, hypotension, and fever. Severe traumatic injury can lead to critical illness–related corticosteroid insufficiency (CIRCI), where an exaggerated proinflammatory response is paired with a blunted adrenocortical response. CIRCI is associated with HPA axis dysregulation and tissue resistance to corticosteroids; laboratory findings include hypoglycemia, hyponatremia, and hyperkalemia. Proinflammatory effects are further modulated by MIF, which counteracts the anti-inflammatory activity of glucocorticoids and correlates with TBI severity and nonsurvival.

Metabolic and immunomodulatory effects are also driven by Growth Hormone (GH), which promotes protein synthesis and insulin resistance. GH acts through insulin-like growth factor-1 (IGF-1) to improve metabolic rates and protein loss after injury. While GH levels are often suppressed during critical illness, exogenous administration in severely burned children has proven beneficial, though it has been associated with increased mortality in other critically ill adult populations. Ghrelin, an appetite stimulant, also exerts anti-inflammatory effects through the CNS and the "cholinergic anti-inflammatory pathway," and high levels have been shown to predict ICU survival in septic patients.

The sympathetic nervous system response to injury results in a surge of epinephrine (EPI) and norepinephrine (NE) from the adrenal medulla. These catecholamines prepare the body for the "fight or flight" response, increasing heart rate and blood pressure while mobilizing glucose through glycogenolysis and gluconeogenesis. To compound this, insulin release is decreased, leading to hyperglycemia, which contributes to the proinflammatory response. However, catecholamines also play a role in reestablishing homeostasis; for instance, high doses of epinephrine can inhibit TNF-alpha and enhance IL-10 production. Immune cells like macrophages and T cells express adrenergic receptors, allowing catecholamines to regulate immune functions directly.

Aldosterone, a mineralocorticoid, regulates extracellular volume and blood pressure by stimulating sodium reabsorption and potassium excretion in the kidneys. It also affects the immune system, where its receptor (MR) is found on monocytes and neutrophils, often inducing the secretion of proinflammatory cytokines in dendritic cells. Insulin resistance and hyperglycemia are hallmarks of critical illness, driven by catecholamines and cortisol. Hyperglycemia is predictive of increased mortality in trauma patients as it alters leukocyte functions and increases infection risk. While insulin therapy is used to manage this, the ideal blood glucose range for critically ill patients remains a subject of debate.

Finally, cellular stress involves Reactive Oxygen Species (ROS) and the Unfolded Protein Response (UPR). ROS are highly reactive molecules that can cause cellular injury but also serve as important signaling messengers in the immune system. They are produced mainly in the mitochondria and by NADPH oxidases (NOX), and their synthesis is triggered by inflammatory mediators like TNF. ROS influence the NLRP3 inflammasome and can regulate immune cell signaling through phosphorylation events. The UPR is a mechanism triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It attempts to restore homeostasis but can also result in cell death, the acute phase response, and the activation of NF-κB if the stress is significant. ER stress markers have been demonstrated in burn patients and animal models of hemorrhagic shock.