Generation inflammation

The past few decades have ushered in a metamorphosis of the field of immunology. Whereas the fundamental role of the immune system in the defense against infectious disease is well-established, only recently have investigators begun to uncover its equally significant association with non-communicable disease. Inflammation is increasingly implicated in the etiology and progression of numerous “modern diseases of affluence,” eliciting both excitement and apprehension from scientists and non-scientists alike. In popular culture, the topic has joined the ranks of GMOs, calories, and climate change—scientific ideas that are widely known yet just as widely misunderstood. As such, the market for “anti-inflammatory” products is burgeoning, ranging from supplements to crystals. All this begs the question: what really is inflammation, and what role does it play in the development of disease?

The primary job of the immune system is to protect the body from potentially harmful intruders, or pathogens. Broadly speaking, this action is enabled by receptors on immune and other cells that recognize noxious materials called antigens. Upon antigen recognition and activation of downstream signaling cascades, a typical immune response comprises two waves of interdependent events.

If the scene of the crime is the site of infection, the cells of the innate immune system (namely macrophages and neutrophils) are the first responders. The innate arm of immunity is a rapid and highly conserved yet nonspecific system designed to recognize patterns expressed by a wide variety of pathogens. Although the innate immune response cannot determine the specific identity of a pathogen and thus may not be able to fully clear it, it functions to contain the infection in order to mitigate damage and buy time to call for backup from the adaptive immune system.

This second wave of adaptive immunity mainly comprises lymphocytes—T and B cells—which contain highly-specific receptors capable of recognizing sequences unique to each pathogen. Each lymphocyte contains thousands of receptors of the same specificity, which is randomly generated through the rearrangement of gene segments. In fact, over 100 million specificities are produced—more than there are unique antigens in the world!

Normally, lymphocytes are continuously patrolling the body by means of the lymphatic system, sampling elements with their receptor in search of their respective antigen. Notwithstanding this enormous receptor variety, only one or a few cells of each specificity exist in the body, meaning that it takes some time (usually a few days) before the right cell finds the pathogen. The adaptive immune response involves cloning the activated lymphocyte (through clonal selection) to give rise to more cells that are able to target the pathogen and thereby efficiently resolve the infection. Unlike the innate system, adaptive immunity is also capable of generating memory, meaning that subsequent re-infection will result in faster clearance—often even before clinical symptoms arise—as more cells and antibodies with specificity for the pathogenic antigen are present in the body. Such immune memory is the basis for vaccines.

Inflammation is the damage control process by which the innate immune response attempts to temper the infection and ramp up the adaptive immune response. This “alarm signal” can be local or systemic, depending on the nature of the infection. Activated innate immune cells secrete messenger proteins called cytokines (among other mediators), which can travel near and far to bind receptors on both immune cells and other cell types to elicit responses; notably, to attract them to the site of infection so the specific lymphocyte has a better chance of finding the pathogen. Cytokines also facilitate physiological changes such as increased blood vessel diameter and permeability to allow large numbers of immune cells to rapidly access the site of infection.

There are both pro-inflammatory and anti-inflammatory classes of cytokines, and is it the balance between these subtypes that determines the functional state and intensity of the immune response. Immune cells clear pathogens via a variety of potent mechanisms, including but not limited to: cell destruction (lysis), engulfing and breaking down noxious materials (phagocytosis), production of harmful reactive oxygen species, and secretion of toxic molecules. As such, inflammation is quite an unpleasant experience, characterized by five “cardinal signs”: redness, swelling, heat, pain, and loss of function.

Though inflammation is essential for survival, it’s important to emphasize that this is a precarious cost-benefit trade off. The innate immune response was designed to operate for short bursts of time. Accordingly, infected or damaged cells are sacrificed for the greater good of the tissue and/or organism, and any collateral damage and discomfort is transient. However, in contrast to this acute inflammatory response, in our modern Western society, many individuals exhibit a low level of chronic inflammation, characterized by a preponderance of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-alpha, and IL-1β. Due to the formidable potential of cytokines to induce loss of tissue function and coordinate immune responses, chronic inflammation is typified by the disruption of homeostatic mechanisms and damage to body systems.

But why does this chronic inflammation arise? If the inflammatory response occurs in reaction to a noxious stimulus, then it follows that chronic inflammation is the result of a persistent threat. Said differently, the body is constantly on high alert; however, the offender is often not a pathogen. Instead, persistent inflammation is thought to arise because humans are not well adapted to our modern environment and lifestyles. Across millions of years of evolution, the human body, including the foregoing immune trade-off, has been finely tuned through natural selection for optimal function in its environment. However, genetic adaptation requires prolonged exposure to novel environmental stressors. As much as we like to flatter ourselves by calling humans the most “highly-evolved species,” recent technological developments and urbanization have far outpaced our ability to adapt to our rapidly changing environment. As such, we are operating under the auspices of outdated systems—like judging a fish by its ability to climb a tree.

The human nervous system was designed to react to primitive threats; due to the fundamental mismatch between the paleolithic environment for which the human body is optimized and the typical Western lifestyle, we tend to experience physiological reactions to novel cultural phenomena. On a subcortical level, we perceive social stressors—mortgage payments, divorce, exam scores—as fundamentally life-threatening. Moreover, it’s often the same factors that we consider “modern luxuries”—agriculture, the Western diet, antibiotic use, etc.—which actually function as niche constrictions (making alterations to the local environment to suit our needs), causing rapid and frequent changes to our immediate environment.

It’s an ironic betrayal that our attempts to better our lives through innovation have been met with such biological resistance. Taken to a more specific level, the modern triggers for chronic inflammation are manifold: sedentarism, epigenetic modifications, obesity, childhood circumstances of adversity, abuse, microbial exposure, disturbances in microbiome composition, poor diet, social isolation, stress, socioeconomic deprivation, sleep disturbances, air pollution, and cigarette smoke. These processes cause damage or dysregulate processes within the body in many different ways, triggering constitutive and inappropriate activation of the immune system. At its core, chronic inflammation is a maladaptive response. 

Because physiological processes can only occur within certain conditions, the human body is designed to maintain homeostasis: the regulation of bodily parameters within a range around a set point. Examining this maladaptive inflammatory response through the prism of physiology, changes in either the internal or external environment are sensed and elicit precise counterregulatory responses. The process of restoring homeostasis is called allostasis, and involves various systems and chemical messengers, including inflammatory mediators such as cytokines. For example, an infection disturbs homeostasis, and the immune system is induced to restore it at the cost of temporary damage. Allostasis is an energetically costly process, and when continually overactivated—such as in the case where the human body is constantly attempting to compensate for our modern environment—it leads to the increased accumulation of what’s known as allostatic load, or “wear and tear” on the body. Within the context of this paradigm, inflammatory mediators of allostasis tax and subsequently damage various biological systems at the organ, tissue, and cellular level, and this damage is the rudiment of disease. 

A battery of studies have implicated chronic inflammation as part and parcel of metabolic syndrome, type 2 diabetes, liver disease, cardiovascular disease, mood disorders, neurodegenerative diseases, and some cancers, among many others. Taken together, these conditions account for over 50 percent of all deaths: the most significant causes of global morbidity and mortality. What is even more striking is the outsized incidence of comorbidity among many of these disorders, suggesting they may not be comorbid, but rather different manifestations of the same underlying problem.

Admittedly, I’ve attempted to paint a reductionist portrait of an irreducible phenomenon. Inflammation is incendiary, unleashing pathologic chain reactions across many of the body’s systems, which may in themselves be dysregulated as a function of maladaptation. Therefore, despite tremendous inroads that have been made towards understanding this process, inflammation remains somewhat of an elusive alchemy. Due to the wide array of cells and molecules implicated within this umbrella term, as well as the manifold biological consequences, no singular biomarker exists. Moreover, although meta-analyses have demonstrated various beneficial effects of anti-cytokine therapies (e.g. reducing insulin resistance, anti-depressive effects), due to the critical importance of inflammation, significant side effects exist, such as increased infection risk and susceptibility to cancer.

Targeting inflammation is further complicated by the redundancy of cytokine actions, as well as by inconsistency with respect to patient response (e.g., due to genetic factors). Although numerous other specific and non-specific drugs such as NSAIDs, corticosteroids, statins, some antidepressants, some antibiotics, and supplements including omega-3-fatty acids and N-acetyl cysteine are indicated for certain inflammatory conditions, currently there is no pharmacological panacea. However, what is under-emphasized is the importance of lifestyle. Exercise has been proven to be anti-inflammatory, as is proper sleep hygiene and a healthy, balanced diet.

Moving forward, investigating inflammation to unravel its role as a shared etiological factor of many non-communicable diseases will not only require the scrutiny of organismal, cellular, and molecular-level mechanisms, but the cooperation of basic scientists and clinicians across diverse specialities. Furthermore, evolutionary considerations warrant examining the frame of human existence not just within the present, but the past and the future. Extrapolating from current trends, future innovation and modernization threaten to exacerbate the burden of non-communicable disease. Therefore, as a society, we need to find the fine line between making our lives more comfortable and making our lives better.