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Pathomechanism

The Connection Between Inflammation and Disease

What does the inflammatory response have in common with a turtle?


Inflammation is a term that many use, but very few actually understand. Because of its endogenous origin and near universal association with disease, it is tempting to jump to reductionistic conclusions that makes the human body look really dumb.1)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601794/ It has already been firmly established that inflammatory activity causes tissue-damage, and that anti-inflammatory treatment-regimes can halt progression in select cases of inflammatory disease, so it would be easy from here to make a case for biologic imperfection, and to conclude that the body sometimes needs to be protected from itself with targeted pharmacological intervention.2)https://www.sciencedirect.com/science/article/pii/S10634584090025073)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241942/4)https://pubmed.ncbi.nlm.nih.gov/25651945/5)https://pubmed.ncbi.nlm.nih.gov/8938281/

But if we first stop to think, and consider why it is that natural selection has allowed such a response that is so clearly damaging to our cells and tissues to evolve and persist, and also why it was picked as our main defence against noxious environmental stressors, perhaps then we can start to see if there maybe is some underlying purpose to this or if it is indeed simply a flaw.

If it’s is flaw, then its a big one, since its observed with defensive-reactions in all complex organisms, even in plants.6)https://link.springer.com/article/10.1007/s00425-018-2956-0?shared-article-renderer This means that multicellular organisms that did not have this trait of self-harm, to sacrifice short term health in parts for long-term survival of the whole got extinct, implying that it literally might be an essential genetic feature. However its universal prevalence does not completely disprove the argument of biologic imperfection, that its a flawed response and that insufficient selection-pressure potentially gave it a free pass through the course of evolution. or the idea that in some select diseases like rheumatoid arthritis (RA) it’s just a randomly occurring genetic defect. Since this is hard to definitely disprove, I will instead present another perspective that to me seems to make more sense from an evolutionary-biology perspective.

A Defensive Feature, not a Flaw.

In the previous chapters I’ve been progressively making a case for the inflammatory response seen with non-communicable chronic disease being chiefly a response to a growing infectious threat coming from the gut-, cutaneous or mucosal microbiome. Since microbes can infect tissues as well as cells, the ability to cause autologous damage could be considered a feature related to infectious defence, although as mentioned in previous chapters it might also be exploited by pathogens. If this is true with non-communicable disease, then it means that anti-inflammatory treatment-regimes will reduce symptoms sometimes at the expense of lowered defensive functions compromising an attempt to keep invading pathogens away, hence increasing the risk of severe infection.

Inhibiting Damage Risks Infection.

In basic support of this, studies of diseases with strong autoimmune features, like RA have shown reduced diversity of the commensal microbiome and there is also evidence of microbial presence in joint-tissues from these patients that differs from control-samples.7)https://www.frontiersin.org/articles/10.3389/fcimb.2019.00369/full8)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155189/9)https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225110 The overall picture seems to be that these microbes originate from the oral cavity or from the gut-microbiome, but it is also possible that they can come from other host-microbial interfaces, like the lower airways.10)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789258/11)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495574/12)https://pubmed.ncbi.nlm.nih.gov/27974664/13)https://pubmed.ncbi.nlm.nih.gov/29221594/ More importantly, and in support of the above assertion that an autoimmune-like phenotype can be a defensive trait in response to a major infectious threat, rheumatic patients are at an elevated risk of severe infections that require hospitalisation which increases with disease-severity and dose of pharmacological treatment, varying also by type of medication with some raising the relative risk more than three-fold.14)https://rmdopen.bmj.com/content/5/1/e00093515)https://pubmed.ncbi.nlm.nih.gov/28422773/16)https://www.sciencedirect.com/science/article/abs/pii/S156899720800077317)https://www.sciencedirect.com/science/article/pii/S014067361461704918)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858027/19)https://academic.oup.com/rheumatology/article/46/7/1157/2899485

Self-Starvation Preceding Self-Destruction.

In most cases however, our primary and initial defence against pathogens is not all-out self-destruction, but instead starts with a state of self-starvation. The body’s main concern with microbes is parasitic infection, hence by limiting its own access to nutrients, it also limits the loot available to actual or potential invaders. At the level of the organism this is mirrored in behaviour and is seen most clearly and frequently in severe infectious states and is termed “infectious anorexia” expressed as a voluntary reduction or complete cessation of nutrient intake to starve a pathogen and is often coupled with mobilisation of internal resources.20)https://pubmed.ncbi.nlm.nih.gov/283688/ It is an essential response that is evolutionary conserved from our last common ancestor with insects and is a part of a broader arsenal of physiological and behavioural responses to infection categorised as sickness-responses.21)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079534/ The common denominator of most of these responses is that they affect energy-utilisation. For example locomotor activity is reduced through induced feelings of lethargy, and the mechanisms upholding homeothermy are altered by causing the subject to feel cold as a signal seek out external sources of heat.22)https://pubmed.ncbi.nlm.nih.gov/8304533/23)https://www.nature.com/articles/s41577-019-0159-y Both these mechanisms are ways to save energy for processes related to the immune-system, and to lessen the need for nutrient intake which could potentially aggravate an ongoing parasitic threat of gastrointestinal origin. Some of these disease-related behaviours can be observed in chronic non-communicable disease, albeit not as clearly or frequently as in sever infection. In the example of RA pain-levels seem to track along with symptoms of fatigue, without one causing the other, implying that the two symptoms originate from the same source.24)https://onlinelibrary.wiley.com/doi/full/10.1002/acr.21932 Patients with widespread musculoskeletal pain have a 20-fold higher risk of also experiencing symptoms of chronic fatigue. This relationship persisted with an 10-fold increase in risk after controlling for genetics, where as the connection that was found with psychiatric co-morbidity, like depression and anxiety disappeared, challenging the popular notion that chronic pain is just a psychosomatic phenomenon.25)https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/41079426)https://pubmed.ncbi.nlm.nih.gov/12415604/ Fatigue is also a common symptom of other chronic diseases and has shown to be related to inflammation.27)https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00078/full

Tissue Sickness-behaviour.

In the case of chronic non-communicable disease, sickness-related behaviours like fatigue is more readily observed at a tissue-level, and in many ways the overall pathophysiological picture seems to bear resemblance to what happens with the septic response in severe infection. For example, muscle-cells taken from patients that died of sepsis shows decreased levels of cellular energy (ATP) compared with survivors, and indeed this is exactly what is also observed in chondrocytes taken from diseased cartilage in osteoarthritis which implies that fatigue or decreased activity potentially can be said to be part of the cellular sickness-response as well as at the level of the organism.28)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079534/29)https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20149 Reduced cellular energy-levels doesn’t look to be the result of a defect or damage, rather it seems to be an active choice of the organism. In support of this, experimental induction of lethal sepsis by injection of traces of dead bacteria, lipopolysaccharide (LPS) causes death in the organism by way of endogenous mechanism connected to the inflammatory response, not through the direct toxicity of the substance.30)https://pubmed.ncbi.nlm.nih.gov/8330903/ Contrary to popular opinion, LPS isn’t a toxin, and it does not passively leak through cellular junctions but is instead voluntary and actively imported into the bloodstream from host-microbial interfaces. Sub-lethal injections even seems to confer protection from subsequent infection with live bacteria which implies that LPS-sensing is a way for the body to scan its immediate environment for potential threats so it can prime its responses accordingly.31)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754132/ Still, in the absence of deeper evolutionary reasoning it can seem very strange that the body essentially kills itself instead of risking subjugation by a pathogen, but the alternative would then be to submit to excessive parasitic control, which essentially means that the host would have to give its genes away to serve the parasites lineage instead of its own. A state of total submission and slavery, which even by present human narratives is considered “a fate worse that death”.

The Principle of Energy-Partitioning.

A previous paradox was that when muscle-cells was simulated with LPS in-vitro there were conflicting results and often were increased rather than decreased ATP-synthesis observed, which was in direct opposite to what was seen in cell-samples taken after systemic LPS-injection. This was later resolved by adjusting experimental conditions as to mirror local tissue milieu, culturing the muscle-cells with a conditioned medium from LPS-stimulated immune-cells which gave a cellular energetic phenotype that matched the pathophysiological picture with reduced ATP-production.32)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851226/ This means that the cellular sickness-response is in large part mediated by the immune-system, and not directly by signals from pathogens. Immune-cells exist on the outside of our tissues and chiefly interact with non-immune cells through secretion of cytokines which can be both pro- and anti-inflammatory. These molecular signals seems in part to be a way for immune-cells to regulate energy-partitioning between themselves and the tissues, with pro-inflammatory-cytokines driving energy towards cells of their own kind, while anti-inflammatory signals instead passes them over to the tissues. This is a two-way communication-line, and non-immune-cells can also synthesise and secrete cytokines for the same purpose. One of the more studied ones of the pro-inflammatory category is TNF-a which is chiefly synthesised by host phagocytes, and it has been shown to be a key part in both the low-grade systemic inflammation that is seen with chronic non-communicable disease as well as in the septic response, mediating both the lethal and priming effect in the previous example.

This cytokine has roots going back more than 500 million years to a common ancestor with corals and arthropods, and the mechanism of effect seems to be so well-conserved evolutionary that TNF-a produced by corals has shown to be able to cause cell-death in humans and conversely TNF-a synthesised by humans has shown to be able to cause the same effect in corals.33)https://www.pnas.org/content/111/26/9567. This highlights the ancient nature of the perceived negative effects of inflammation.

Immuno-Mechanical Cross-Talk.

The decreased ATP-production seen with TNF-a stimulation in-vitro seems to be paralleled with increased non-oxidative metabolism of glucose and subsequent lactate-production, a process known as the “Warburg-effect” in cancer-research.34)https://www.sciencedirect.com/science/article/pii/S092544391300100235)https://pubmed.ncbi.nlm.nih.gov/25710281/ Lactate then leaves the cell, which causes a net-loss of potential energy since glucose was not fully oxidised. However, suitingly lactate can be used as fuel by active phagocytes on the outside, and they show up-regulation of cellular lactate import-receptors (MCT1) upon LPS-stimulation which implies that lactate is used in inflammation-related processes.36)https://pubmed.ncbi.nlm.nih.gov/8436827/37)https://www.ncbi.nlm.nih.gov/pubmed/10774612 Stimulation of macrophages with LPS also causes up-regulation of membrane-bound glucose-channels (GLUT1), and secreted TNF-a causes insulin-resistance in surrounding non-immune cells.38)https://pubmed.ncbi.nlm.nih.gov/8557327/39)https://pubmed.ncbi.nlm.nih.gov/16186396/ This causes the extracellular glucose-concentration to increase, which then allows glucose to be internalised by phagocytes and other immune-cells which chiefly uses diffusion for glucose-uptake. Up-regulation of GLUT1 by TNF-a stimulation also occurs in non-immune cells , like skeletal muscle which normally uses insulin-dependant uptake via GLUT4 which in contrast to GLUT1 can regulate glucose uptake through negative feedback to suit metabolic needs. This explains the in-vitro paradox where stimulation of muscle-cells by TNF-a is seen to cause an increase in glucose uptake and metabolism by these cells while simultaneously causing them to become insulin-resistant.40)https://pubmed.ncbi.nlm.nih.gov/9832415/41)https://pubmed.ncbi.nlm.nih.gov/25710281/ The shift towards GLUT1 and uptake by diffusion still allows glucose to enter the muscle-cells as to uphold homeostasis but the majority will be diverted to immune-cells hence causing a “lethargic phenotype”. In general it can be said that glucose uptake in insulin sensitive tissues is regulated by demand for mechanical work, increasing receptor-mediated glucose uptake via GLUT4 which is then enhanced in the presence of insulin. Within the immune-system, inflammatory cytokines is instead what signals increased metabolic demand, driving glucose uptake. In this way energetics of mechanical tissues and functions is at odds with that of inflammatory cells and their respective functions. This explains for example why elite-athletes seems to be at higher risk for infections during periods of extremely high training-loads and intensity.42)https://pubmed.ncbi.nlm.nih.gov/19336500/

Septic Mimicry.

Evidence of these mechanisms of intercellular nutrient-partitioning is seen very clearly with the septic response where increased hepatic production of glucose is paralleled by systemic insulin-resistance in muscle and adipose-tissue that causes hyperglycemia, hence diverting glucose towards red- and white blood-cells, both which has important roles in the systemic infectious defence, and use insulin-independent glucose uptake by diffusion through GLUT1-channels.43)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029293/44)https://pubmed.ncbi.nlm.nih.gov/9681995/45)https://www.jimmunol.org/content/180/7/4476 Increased lactate-production is also observed systemically, and is related to decreased survival, perhaps mirroring the severity of the inflammatory stimulus.46)https://pubmed.ncbi.nlm.nih.gov/27380535/ Apart from fuelling resident phagocytes, increased lactate-production by non-immune cells in this context might also be a way to drive gluconeogenesis in the liver to meet the high demands for glucose by activated immune-cells.47)https://www.ncbi.nlm.nih.gov/pubmed/29476613

Inflammatory Pain as an Adaptive Response.

In the case of chronic non-communicable disease, there is also ample evidence of inflammatory-related energy-partitioning, and signs of inflammation can for example be found around painful muscles together with elevated levels of extracellular lactate which is also a characteristic finding.48)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062547/ Interestingly, studies have also shown that phagocytes seems to be the link between fatiguing muscular insults and pain, and depletion of macrophages are seen to block the hyperalgesic response.49)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499332/ Perhaps this means that pain in this case is a cellular protective mechanism, a way for the body to signal to the brain that the affected tissue is energetically compromised by resident phagocytes that are trying to respond to an inflammatory stimuli, either infectious on non-infectious. Elevated levels of lactate has also been observed in other musculoskeletal diseases, like RA where increased lactate-concentration can be measured in synovial tissues, which in turn has been shown to cause increased immune-cell activity.50)https://www.nature.com/articles/s41584-019-0344-1

Immunological Barricades.

The inflammatory-response chiefly takes place outside of host tissues in the extracellular matrix and it can be seen to generate what can be likened to an immunological barricade around the parenchymal cells that is composed of connective-tissue, a phenomenon known as fibrosis.51)https://pubmed.ncbi.nlm.nih.gov/30072398/52)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081658/53)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127292/ Together with  the increased presence of leukocytes and fluid-accumulation this can further complicate transport of nutrients and oxygen to the parenchymal cells.54)https://journals.sagepub.com/doi/10.1177/026835559000500403 This also follows the principle of energy-partitioning as previously explained, but it means that for avascular tissues like articular cartilage which depends on oxygen diffusing through the radially situated fibrous capsule and nutrients getting transported via synovial fluid produced by cells of the inner capsular membrane, inflammation of the capsule can cause oxygen- and nutrient-deficiency in cells that reside in the joint-cartilage that is of a different nature than when cells receive a direct inflammatory stimuli.

Cellular Self-Defence.

The anti-infectious functions of the inflammatory response however isn’t just driven by the immune-system and there are several ways in which all cells can directly defend themselves, but this also seems to happen at the compromise of their own health in the short term. These cellular defense-mechanisms are characterised by alterations in cellular membrane-structure, internal milieu and behaviour, and seems to be in mimicry of a phagocytic cellular phenotype. Instead of taking in nutrients from the blood in the form of sugars, amino acids and lipids, the cells changes its internal milieu as to resemble a stomach by up-regulating mitochondrial synthesis of reactive oxygen species (ROS) as well as other catabolic-related substances, and by forming special membrane-lipids it can start digesting its own contents to gain nutrients while simultaneously also gaining an enhanced ability to use endocytosis to swallow components of the surrounding extracellular matrix as well as invading pathogens. 55)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2242731/ This shift in the chief mode of nutrient-supply from normal diffusion and receptor-mediated extraction from the periphery to instead more of a digestive-like metabolism is usually termed “macro-autophagy”, here after only referred to as simply autophagy, meaning self-eating (or xenophagy, when digesting a pathogen). This is an essential survival-mechanism and is thought to be evolutionary conserved from the last common eukaryotic ancestor.56)https://pubmed.ncbi.nlm.nih.gov/17977463/ The shift in cellular membrane-structure is characterised by increased levels of sphingolipids and ceramides with the transition towards autophagy, and the initial discovery of these substances and their association with effects such as insulin resistance and programmed cell-death labeled them with a large bulls-eye for pharmacological treatment. However, since both sphingolipid and ceramide are synthesised endogenously it seems appropriate to investigate if they perhaps have a functional purpose.

Submergence as a Metaphor

A potential clue comes from the fact that these lipids are shown to mediate the response to both biotic and abiotic stress, in humans as well as in plants. In plants, sphingolipids and ceramides has shown to be protective against conditions of both cold, drought and under-water submergence and since the same class of molecules is shown to be involved in the response to infection we can infer that the defensive mechanisms might also be somewhat similar, at least in part. 57)https://www.sciencedirect.com/science/article/pii/S1674205218303058 A way to increase endurance to an external threat. The mechanism could perhaps be compared to anticipating being suddenly submerged under water by taking a deep breath, and then holding it while minimising unnecessary energy expenditure as to avoid drowning, hoping to at some point be rescued by a life-guard or that the water will drain. In short, maximising the ability to utilise internal resources. In support of this notion, lethal injection of LPS are seen to cause death in normal mice within 30 hours, while death occurred within only 10 hours in mice modified to have an impaired ability to form ceramides.58)https://www.ncbi.nlm.nih.gov/pubmed/26183206 The ability of autophagic processes to promote survival in harsh and scarce external conditions has led many researchers to compare the mechanism with the physiology of mammalian hibernation, and autophagy might hence be another example of a behaviour that is mirrored at both the cellular level and at the level of organisms.59)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755359/

Another function of sphingolipids and ceramides is to enable enhanced capacity for endocytosis, of both endogenous macromolecules as well as pathogens (both for better and for worse..) through acting as attachment-points and important structural components related to formation of the endosome.60)https://www.frontiersin.org/articles/10.3389/fcell.2019.00203/full61)https://pubmed.ncbi.nlm.nih.gov/30060813/

Phenotypic Miss-Matching.

Besides the obvious catabolic effects on both cells and tissues that comes as a consequence of autophagic cellular physiology, there are also other detrimental effect that occurs by the changed phenotype miss-matching their normal physiological purposes, and an inflammatory cellular phenotype might hence be a predisposing factor to injury. In muscle-cells, increased amounts of sphingolipids and ceramides has been shown to negatively affect muscular energetics and hence also contractile function leading to weakness and pre-mature fatigue.62)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851226/63)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176343/

Sterile Inflammation?

Finally there is also the process of sterile inflammation. The most common form of experiment investigating this is ischemic re-perfusion-injury. Anti-inflammatory treatment has here been shown to stave off resultant tissue-injury, which is thought to be beneficial, however there has not been research done as to the quality of the prevailing tissue which could potentially be severely affected with lingering damage to genetic material predisposing to mutations. But this is still merely speculative.

Summary.

To sum up. Inflammatory processes has many effects that are clearly disadvantageous and harmful to endogenous cells and tissues in the short term, but the mechanisms that cause these effects in turn seem to help to preserve the integrity of the whole organism in the long term. Interference with these mechanisms in an attempt to treat inflammatory diseases might hence have undesired consequences. If we accept that the damaging effects of inflammation have a deeper purpose that just simply representing collateral-damage, we can instead look to what triggers this response in the first place, which I’ve outlined in the previous two sections of this chapter.

A Closing Metaphor.

Reconnecting with the title-image, a fitting metaphor for the workings of inflammation is the behaviour of a turtle. In the case of an external threat, lets say a hungry fox, the turtle retreats into its shell where it its reasonably safe, but with increasing frequency or length of shell-time, the amount of time available to scavenge for food decreases reciprocally. Thus, if the threat is persistent or frequently re-occurring, the turtle can be forced into a state of starvation, where it instead increasingly has to rely on mobilisation of stored resources for survival. The motive of the turtle for this self-imposed state of starvation is not actually to starve itself, but the fox, until he gives up or is taken by another predator. Should the turtle instead be persuaded to come out, for example by his peers who thinks he’s being a coward, or by the state of starvation reaching a critical point, it will be taken by the fox. So, to have a normal life, the turtle needs to cultivate the ability to co-exist with other species in a sometimes hostile and highly competitive environment, and trust his instincts more than his know-it-all peers.

Next section (a summary)

Per Bylund
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