Inflammation-Nature's Way to Efficiently Respond to All Types of Challenges: Implications for Understanding and Managing "the Epidemic" of Chronic Diseases

Abstract

Siloed or singular system approach to disease management is common practice, developing out of traditional medical school education. Textbooks of medicine describe a huge number of discrete diseases, usually in a systematic fashion following headings like etiology, pathology, investigations, differential diagnoses, and management. This approach suggests that the body has a multitude of ways to respond to harmful incidences. However, physiology and systems biology provide evidence that there is a simple mechanism behind this phenotypical variability. Regardless if an injury or change was caused by trauma, infection, non-communicable disease, autoimmune disorders, or stress, the typical physiological response is: an increase in blood supply to the area, an increase in white cells into the affected tissue, an increase in phagocytic activity to remove the offending agent, followed by a down-regulation of these mechanisms resulting in healing. The cascade of inflammation is the body's unique mechanism to maintain its integrity in response to macroscopic as well as microscopic injuries. We hypothesize that chronic disease development and progression are linked to uncontrolled or dysfunctional inflammation to injuries regardless of their nature, physical, environmental, or psychological. Thus, we aim to reframe the prevailing approach of management of individual diseases into a more integrated systemic approach of treating the "person as a whole," enhancing the patient experience, ability to a make necessary changes, and maximize overall health and well-being. The first part of the paper reviews the local immune cascades of pro- and anti-inflammatory regulation and the interconnected feedback loops with neural and psychological pathways. The second part emphasizes one of nature's principles at work-system design and efficiency. Continually overwhelming this finely tuned system will result in systemic inflammation allowing chronic diseases to emerge; the pathways of several common conditions are described in detail. The final part of the paper considers the implications of these understandings for clinical care and explore how this lens could shape the physician-patient encounter and health system redesign. We conclude that healthcare professionals must advocate for an anti-inflammatory lifestyle at the patient level as well as at the local and national levels to enhance population health and well-being.

Keywords: anti-inflammatory lifestyle; chronic disease; clinical care; complex adaptive systems; inflammation; interdisciplinary; stress.

Figure 1

The outcome of any inflammatory response is dictated by the balance between pro-inflammatory and anti-inflammatory factors. Each of these opposing pathways is mediated by different cytokine and hormonal influences. For example, inflammation is favored by IL-1β, IL-6, and TNF-α, whilst being inhibited by IL-10 and TGF-β. The distinctions are not absolute and can vary based on the context. However, excess or chronic inflammation is seen in conditions where the mechanisms mediating homeostasis and balance between the two pathways become compromised. IL1α, interleukin-1alpha; IL-1β, interleukin-1beta; TNF-α, tumor necrosis factor-1alpha; IFN-γ, interferon-gamma; IL-6, interleukin-6; IL-17, interleukin-17; HSP70, heat shock protein 70, CRP, C-reactive protein; IL-4, interleukin-4, IL-1, interleukin-1, TGF-β, transforming growth factor-beta.

Figure 2

Feedback loop between the somatic and central nervous system components of the inflammatory response [exogenous cytokines are typically synthetically made cytokines used as treatment for a variety of immune-related diseases like IFN-α for hepatitis C infection or IL-2 for renal cell carcinoma; adapted from Dantzer (1)].

Figure 3

The main brain-immune system pathways and feedback loops illustrating the interconnected effects of physical and emotional stress in health. Sympathetic nervous system (SNS) activation facilitates immune cell activity and systemic immune responses, while the parasympathetic nervous system (PNS) and the hypothalamic-pituitary-adrenal (HPA) axis generally inhibit inflammatory responses. In a well-regulated system, cortisol provides negative feedback to the HPA axis. Chronic activation of the stress response systems can lead to excessive immune cell activity and promote system inflammation due to the reduced activity of cholinergic anti-inflammatory pathway and development of glucocorticoid insensitivity. Cytokines regulate autonomic nervous system function and the HPA axis as well as induce sickness behaviors. The brain receives information about systemic inflammation levels via the afferent vagal nerve and “leaky” portions of the blood brain barrier especially near the circumventricular organs and these messages influence cytokine production within the brain. Often elevated systemic inflammation increases glia production of cytokines. CRP, C-reactive protein; AVP, arginine vasopressin; TRH, thyrotropin-releasing hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; TSH, thyroid stimulating hormone; PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor; LC, locus coeruleus; C1 & C2, adrenergic cell groups in brainstem; A1& A2, noradrenergic cell groups in brainstem; T4, tetraiodothyronine; T3, triioidothyronine; DHEA, dehydroepiandrosterone; SNS, sympathetic nervous system; PNS, parasympathetic nervous system; BM, bone marrow; LN, lymph node; T, thymus; L, lymphocytes; S, spleen. Dashed lines represent feedback on the brain. In the periphery, solid lines indicate activation, whereas dotted lines represent inhibition.

Figure 4

The wheal-and-flare reaction in the skin. (A) Normal basal or a non-reactive state for mast cells in tissue. The needle injects a known allergic antigen or allergen. (B) Antigens provoking allergic reactions drive specific-IgE production by plasma cells, assisted by TH2 cells. Surface bound IgE on mast cells is cross-linked by secondary exposure to allergen, causing release of preformed (e.g., histamine) and lipid-derived (e.g., leukotriene) mediators which drive the vascular events of allergy (vasodilatation and vascular fluid leak) manifesting as a “wheal and flare.” This photograph depicts a typical wheal-and-flare reaction in the skin in response allergen injection.

Figure 5

The clinical changes and physiological mechanisms of allergic respiratory disease. Antigen-presenting cells (APCs) present allergen-derived peptides lodged within the MHC molecule to T cells within a T_H2 milieu, resulting in allergy mediated by eosinophils and IgE derived from plasma cells (transformed from activated B cells). PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor; MHC, major histocompatibility complex; TCR, T cell receptor; IgE, immunoglobulin E; OX40L, CD252; B7, CD28; IL-4, interleukin-4; IL-5, interleukin-5; IL-13, interleukin-13.

Figure 6

Depending upon the cytokine milieu present at the time of antigen presentation (signal 1) and costimulation (signal 2), three T cell polarization pathways can develop. IFN-γ supports T_H1 deviation that mediates macrophage-mediated reactions. IL-4, IL-5, and IL-13 create a T_H2 environment that drives eosinophil and IgE production. IL-17A, IL-17F, and IL-22 provide aT_H17 environment driving neutrophilic and some autoimmune phenomena. PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor; MHC, major histocompatibility complex; TCR, T cell receptor; IFN- γ, interferon-gamma; IgG, immunoglobulin G; IgE, immunoglobulin E; IL-4, interleukin-4; IL-5, interleukin-5; IL-13, interleukin-13; IL-17A, interleukin-17A; IL-17F, interleukin-17F; IL-22, interleukin-22.

Figure 7

Whereas, normal immunity is marked by tolerance to self-structures (mediated by central and peripheral regulatory pathways), autoimmunity results from aberrant activation of autoreactive T and B cells, responsible for inflammation seen in autoimmune diseases. One mechanism of tolerance breakdown shown in the figure involves impaired clearance of apoptotic debris. IL-2, interleukin-2; IL-4, interleukin-4; IL-6, interleukin-6; IL-9, interleukin-9; IL-10, interleukin-10; IL-17, interleukin-17; TGF-β, transforming growth factor-beta; PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor; MHC, major histocompatibility complex; TCR, T cell receptor; CCR, C-C chemokine receptors; BAFF, B cell activating factor; BAFF-R, B cell activating factor receptor.

Figure 8

Oxidized LDL (oxLDL) activates pro-inflammatory pathways to drive inflammatory changes in coronary vascular disease. LDL, low-density liporptein; oxLDL, oxidized LDL; TLR, toll-like receptors; IL-1, interleukin-1; IL-6, interleukin-6; IL-12, interleukin-12; IL-18, interleukin-18; TNF, tumor necrosis factor; IL-4, interleukin-4; IFN-γ, interferon-gamma.

Figure 9

The inflammatory effects of obesity on insulin resistance, cardiovascular disease and type 2 diabetes—Inflammation results in impaired muscle cell metabolism and insulin insufficiency. MCP-1, monocyte chemotactic protein 1; IL-1β, interleukin-1beta; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; CCL2, CC chemokine ligand 2; CCL3, CC chemokine ligand 3; CXCL8, CXC chemokine ligand 8; PAI1, plasminogen activator inhibitor type 1; LDL, low density lipoprotein; HDL, high density lipoprotein; ROS, reactive oxygen species; GLUT4, insulin-regulated glucose transporter type 4; CRP, C-reactive protein; FFAs, free fatty acids; IL-1RA, interleukin-1 receptor antagonist; ER, endoplasmic reticulum.

Figure 10

Inflammatory regulation in depression. Inflammatory pathways use the pro-inflammatory NF-κB signaling pathway to drive the neurohormonal changes seen in depression. Reduced glucocorticoid receptor expression and parasympathetic activity leaves immune cells in a primed pro-inflammatory state due to sympathetic nervous system dominance. NF-κB, nuclear-factor kappa-B; CRH, corticoptropin-releasing hormone; ACTH, adrenocorticotropin hormone; a7-nAChR, alpha-7 nicotinic acetylcholine receptor; GCR, glucocorticoid receptor; AR, adrenergic receptor. This figure is an modified/updated version of a previously published figure by Bennett and Sturmberg (144).

Figure 11

Inflammatory pathways in osteoarthritis. Inflammatory pathways use the pro-inflammatory NF-κB signaling pathway to drive the joint changes seen in osteoarthritis. NF-κB, nuclear-factor kappa-light-chain-enhancer of activated B cells; IL-1b, interleukin 1 beta; IL-6, interleukin-6; TNFα, tumor necrosis factor alpha; IL-17, interleukin-17; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; PGE2, prostaglandin E2; NO, nitric oxide; ROS, reactive oxygen species; MMPs, matrix metalloproteases; PTH, parathyroid hormone.

Figure 12

Aging Pathways—chronic low-grade inflammation results in functional decline and frailty. In older age the sudden rise in cytokine load due to an acute infection often results in neuropsychiatric conditions with slow and often incomplete recovery. IL-1β, interleukin-1 beta; IL-4, interleukin-4; IL-6, interleukin-6; IL-10, interleukin-10; TLR, toll-like receptor; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon gamma; PGs, prostaglandins; ROS, radical oxygen species; NO, nitric oxide; NLRP3, nucleotide-binding domain leucine-rich repeat protein 3; ASC, apoptosis-associated speck-like protein containing a CARD; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; DAMPs, damage-associated molecular patterns; UTI, urinary tract infection.