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Conflammation: Too Much Conflation in Inflammation?

Submitted:

18 July 2026

Posted:

21 July 2026

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Abstract
The use of the word inflammation in recent literature appears to have superseded the classical definition of the word. However, a precise new definition has not yet emerged. As a result, the boundaries of the concept are hazy and it needs to be examined critically whether everything in the semantic basket is indeed “inflammation”. Similar to almost all genes, molecules and pathways, inflammation associated cells and molecules also have a number of normal physiological functions unrelated to defence. Therefore, altered expression of these may not always reflect inflammation. If all the range of functions are also to be called inflammation, in the entire life ranging from embryo implantation to death, the body can be said to be always in a state of inflammation. This takes aways the need for the concept itself. As a result of the ambiguous definition, a number of anomalies are associated with the concept of inflammation. In particular the concept of chronic systemic inflammation is laid with multiple anomalies which might be misleading our understanding of health and disease. On the foundation of evolutionary logic, a new and clearer perspective of inflammation can emerge. We discuss the foundations of the new perspective and its relevance to health, disease and medicine.
Keywords: 
inflammation
;  
immune cells
;  
inflammatory markers
;  
pleiotropy
;  
evolutionary immunology
;  
life style related disorders
Subject: 
Biology and Life Sciences  -   Immunology and Microbiology
Inflammation has become a key term in biomedicine used extensively in various contexts, but rather loosely and ambiguously. The concept has undergone a number of major transitions in core definition, working definition, tools for detection and perceived relevance in medicine. A problem arising because of the rapid transitions is that the classical definitions are no more valid but a precise new definition has yet not emerged clearly and unambiguously. The problem goes beyond semantics and affects the conceptual foundations of physiology, immunology and medicine. With huge amounts of genetic, molecular, cellular, metabolic, immunological intricacies coming to light every now and then, the field appears to have lost in details. With the intriguing amount of information, more internal contradictions and conceptual anomalies are accumulating which need to be addressed seriously. We do not claim to resolve the anomalies at one go, but attempt to point out the critical issues that need to be addressed starting with definition and suggest a possible novel platform based on which a coherent sense can emerge.

I. Historical Context of Definition of Inflammation

The definition of inflammation has gone through three major phases of transition. The ancient clinical context of inflammation “Notae vero inflammationis sunt quatuor: rubor et tumor cum calore and dolore” stems back to the 1st century AD defining the four cardinal signs of inflammation, namely redness, swelling, fever and pain by Arnus Cornelius Celsus. The fifth sign, functio laesa or “loss of function,” was introduced later. Influentially, Galen (3rd cent. A.D.) redefined inflammation (Phlogosis) as a reaction of the body against injury. These early ideas were shaped only by the available tools and knowledge of biology and therefore were symptoms based (Cavaillon, 2021; Rocha & Silva, 1978; Russell P. Tracy, n.d.).
Approaching the 19th century, advances in microscopy and cell biology opened the door to second phase, i.e. the cell-based definitions of inflammation. It was for Elie Metchnikoff (1845–1916), that the view on inflammation was shifted to phagocytosis, suggesting that inflammation is a host-defence mechanism, where “phagocytic cells move toward, engulf, and destroy the invader, aided in higher organisms by diapedesis through the blood vessel system.” Neumann (1889) included the healing or restorative component to the definition. In the more inclusive concept, the role of cells was expanded from phagocytosis to many more functions. But for all the vital functions, the first requirement was aggregation of appropriate immune cells at the site of injury. This aggregation was then identified as the core of the inflammation process. At the acute stage of inflammation neutrophils are first in line involved in rapid phagocytosis and pus formation, monocytes differentiate into macrophages & are known to have functions of cleanup, cytokine release and repair initiation at the subacute stage, at the subsequent stage lymphocytes are known to regulate responses and plasma cells to produce antibodies, finally at the resolution stage macrophages, fibroblasts and endothelial cells are required for the functions of healing, angiogenesis, collagen deposition and tissue remodelling.
The molecular mechanisms of all these functions of the cells were being discovered from the middle of the 20th century. Sir Henry Dale in 1930s, primarily reframed inflammation as a process mediated by endogenous active substances (acetylcholine, histamine, catecholamine) formed, synthesized or released by the body. The field advanced further with more and more molecules being discovered one by one such as histamine, leukotaxin (chemokines), bradykinin, interleukins, pyrogenic cytokines, C-reactive protein (CRP), and interferons. (Cavaillon, 2021; Jiménez-Gracia et al., 2026). As a consequence, the end of 20th century shifted the focus from cells to molecules. Today the working definition depends upon showing raised levels of one or a few “inflammatory markers”. It is no more considered necessary to demonstrate cell aggregation, the site of aggregation, phagocytosis or other cell interactions and their actual relevance to defence and healing. Implicit behind this working definition is the assumption that the molecules used as inflammatory markers are specific to inflammation alone and always faithfully represent inflammation as defined at the cellular level. Throughout this phase of the transition, the cellular definition of inflammation has not been formally dismantled. (Cavaillon, 2021; Jiménez-Gracia et al., 2026)
The use of the word inflammation today often appears to relate to anything that “immune cells” do or any altered expression of the molecules labelled “inflammatory markers”. But the ‘anything’ component of the perception needs a critical look.

II. Burden of History, Burden of Simplicity & the Perception Bias

We know today that almost no gene, protein or pathway has a single function. Typically, in physiology a gene or molecule is first discovered in a certain context and gets a name and builds an “image” in that specific context. Later many other functions of the same entity are discovered but still in popular image we continue to perceive the entity in its first discovered context. This is a burden of history that might create a bias in our perception. For example, insulin was discovered in the context of diabetes and glucose regulation. We know today that apart from glucose regulation, insulin has a wide range of functions spanning stem cell maintenance, tissue homeostasis, protein metabolism, angiogenesis, sex, reproduction, memory and behavioral decisions (Kern et al., 2001; Neirijnck et al., 2019; Street et al., 2022; Watve, 2013). But if there is a change in plasma insulin levels, we almost invariably relate it to glucose, insulin resistance and diabetes in some way or the other. Even in the context of glucose regulation, it is clear now that the role of insulin is not as it was perceived classically (Diwekar-Joshi & Watve, 2019; Kulkarni et al., 2017). But rather than acknowledging the more complex and evidence -based picture, diabetes medicine continues to go by the oversimplistic classically perceived role. We continue to perceive the systems as modular although they are shown to work as networks (Kulkarni et al., 2017). Thus, both the burden on history and burden of simplicity shape our perception of a cell, gene, molecule or a pathway. Many more examples illustrate the phenomenon.
Classically understood as a “bone formation marker”, osteocalcin is now known to be involved in multiple functions in the body like that of metabolism, reproduction and brain function. It enhances adiponectin release from adipose tissue, improves glucose tolerance and energy metabolism in muscle. It also supports exercise adaptation by promoting glucose and fatty acid utilization, influences male fertility by boosting testosterone production in Leydig cells, and regulates brain development and cognition through effects on neurotransmitter synthesis and hippocampal growth. (Han et al., 2018; Kulkarni et al., 2017; Moser & van der Eerden, 2019; Srivastava et al., 2022). Still the primary perception of osteocalcin remains in the context of bone health.
Similarly, the “adipose tissue” is a multi-functional endocrine organ, that secretes leptin, adiponectin, and resistin, stores energy, regulates glucose homeostasis, controls lipid metabolism and steroid hormone conversion. The tissue also plays a role in adipokines that influence appetite, insulin sensitivity, blood pressure, and inter-organ communication. In essence, adipose tissue is far more than a fat-storage organ, it is a complex, hormonally active tissue that integrates metabolic, immune, vascular, structural, and behavioural signals across the entire organism. But in our perception, the “primary” function of adipose tissue still remains storage of excess energy. (Barthelemy et al., 2023; Chang et al., 2020)
First known by the observation that it inhibits macrophage migration and hence named the Macrophage Migration Inhibitory Factor (MIF), the molecule is now known to have diverse pro-inflammatory and anti-inflammatory functions. Several studies have demonstrated that MIF has proinflammatory roles for example, it maintains macrophage priming through TLR4 upregulation and acts as a critical autocrine/paracrine regulator of macrophage activation through TLR4 (Roger et al., 2003), it sustains MAPK signalling while overriding glucocorticoid suppression (Mitchell et al., 1999), activates the NLRP3 inflammasome (Lang et al., 2018), it drives chemokine release through CD74 receptor engagement (Takahashi et al., 2009), induces TNF production in monocytes and macrophages (Ranganathan et al., 2017), and enhances NF-kappaB-dependent antimicrobial responses (Roger et al., 2013). It was also found that MIF deficiency results in reduced expression of inflammatory mediators like IL-1β, CCL2, and MMPs, and increased production of anti-inflammatory cytokines such as IL-10 in the lesion area, suggesting that MIF can induce anti-inflammatory effects as well. (Z. Wang et al., 2014). Furthermore, studies have shown MIF to have neuroprotective effects by inducing expression of BDNF. Similarly, MIF is found to upregulate serotonin, THP2 and BDNF in vitro as well as during exercise (Matejuk et al., 2024). MIF was recently found to be released in the ischemic heart, it stimulates AMPK, a master energy-sensing enzyme that increases cellular ATP production and limits energy consumption (Kleemann & Bucala, 2010). Given the span of functions of MIF, the name is a complete misnomer, but still continues to be used and inevitably shapes the perspectives of a person entering the field.
Heat Shock Proteins, first known for the intracellular chaperone functions of protein homeostasis, protein folding and refolding, aiding in the removal of defective proteins, cell signalling transduction, cell cycle, and apoptosis regulation, HSPs also serve as danger signal molecules to alert the immune cells to recognize the existence of damaged cells. (Abreu et al., 2025; Palanivelu et al., 2023)
The diverse examples demonstrate how the cells and molecules are often named in the context of discovery and that often continues to be perceived as their “primary” function. This burden of history and burden of simplicity has haunted the field of immunology too. We see that the cells perceived as “immune cells” have many other functions not directly related to injury and infection. Similarly, molecules primarily discovered in the context of immune function are shown to have other normal physiological functions too. But we are biased in our perception and we continue to see them as “immune cells” and “inflammatory markers”. If we see any change in the population and behavior of cells or expression and standing levels of the molecules, we immediately call it inflammation without considering the possibility that it might be in some other context too. Therefore, we need to look carefully at alternative functions of these cells and molecules and decide whether they always reflect “inflammation”.

III. The Non-Defensive Functions of Immune Cells

The functions of immune cells not directly related to innate immunity are worth highlighting as they are an important part of a system that works like networks, not as modular mechanisms (Goosby & Cheadle, 2024; Navarro Quiroz et al., 2025).
Although macrophages are perceived primarily in the context of immunology, their functions are diverse and start right from embryonic life where infection and injury stimuli are almost non-existent or taken care by the maternal immune system. Macrophages are critical in embryo implantation. Abnormal macrophage distribution, number, or polarization is linked to recurrent implantation failure (RIF) (Sharma et al., 2025) . The placental macrophages of foetal origin, called “Hofbauer cells” play a key role in angiogenesis, vasculogenesis and placental mesenchyme development (Chambers 2021). Interestingly the signals involved in the developmental and re-modelling functions are IL-8 and MMP-9 which are also pro-inflammatory signals in certain contexts.
In adult life, macrophages play an essential role in maintaining tissue balance by clearing dead cells, apoptotic cells, and cellular debris, which helps preserve tissue integrity. This includes efferocytosis, the removal of effete/senescent cells before they trigger more damage. Although this role has parallels with the phagocytosis role in inflammation, it is a part of normal physiology, not triggered by any infection or injury challenge. Furthermore, macrophages play an active role in lipid metabolism and adipose tissue regulation; regulation of ECM and collagen synthesis; angiogenesis; iron homeostasis in the liver; and growth factor expression (Jang et al., 2025; Park et al., 2025).
The name Natural Killer cells is a glaring example of burden of history. The non-destructive functions of NK cells can be traced to reproduction, pregnancy and foetal development. NK cells play a crucial role in facilitating endometrial tissue remodelling, supporting vascular function, and contributing to placental formation. The uterine NK cells, like endometrial NK (eNK) cells and decidual NK (dNK) cells, act as regulators of placentation. They are primarily involved at the maternal-foetal interface in driving angiogenesis on the maternal side and vasculogenesis on the foetal side. The dNK cells regulate uterine spiral artery development, and control the oxygen supply at the maternal foetal interface as well as ensure a good maternal-foetal blood supply. (Chen et al., 2024) . The uterine NK cells secrete osteoglycin that regulates collagen fibril structure and contributes to fetal heart and tissue development (Fu et al., 2017). Improper functioning of dNK cells at the maternal-foetal interface leads to placental dysfunction (Hanna et al., 2006; Martirosyan et al., 2025; Yagel, 2009)
B cells are found to be abundant especially during embryonic brain development. They are directly linked to developing-brain processes and are known to support oligodendrogenesis and myelination. Additionally, B cells are involved in remyelination by producing natural antibodies (nAbs) against unidentified myelin antigens (Halperin et al., 2022; Ihunwo et al., 2022; Rodriguez-mogeda et al., 2022; Tanabe & Yamashita, 2018, 2020; Veremeyko et al., 2024). T cells are involved in complex brain processes including spatial learning, memory, emotional behaviour and stress responsiveness (Morimoto and Nakajima 2019).
Given the span of functions of these cells, calling them “immune cells” appears to be a burden of history. If their role in embryonic development was to be discovered first, we might have called them developmental cells and said that they also contribute to immune function as a secondary role.

IV. Non-Defensive Functions of Inflammatory Markers

Similarly, inflammatory markers also have a set of different functions. It is hence unfair to assume that an altered or elevated level of inflammatory markers is directly linked to inflammation. Exercise for example, triggers high levels of IL-6, but this is not accompanied by elevated IL-1β or TNF-α, the canonical pro-inflammatory cytokines. Instead, exercise-induced IL-6 stimulates molecules like IL-10 and IL-1ra perceived as anti-inflammatory. IL-6 leads muscle to utilize fatty acids and promotes a shift from catabolic, glucagon-dependent pathways to anabolic, insulin-dependent pathways, helping glucose absorption by muscle and contributing to recovery. Thus, IL-6 plays an important role in metabolic regulation in the muscle tissue. It stimulates lipolysis and releases energy sources into bloodstream. It also stimulates insulin secretion and insulin sensitivity. It induces proteolysis in muscle, making amino acids available for protein synthesis. Similar to leptin, IL-6 functions as an indicator of energetic status. Higher levels signal that more energy is available and can be allocated to maintenance functions such as tissue repair. In adipose tissue, IL-6 production may indicate that when stored energy is available it is allocated to somatic maintenance, which is called as “adaptive metabolic allocation”, that has nothing to do with inflammation (Giudice & Gangestad, 2018). Furthermore, IL-6 contributes to appetite suppression and delayed gastric emptying, thereby attenuating postprandial glycemia. Beyond metabolic regulation, IL-6 plays critical roles in skeletal muscle hypertrophy and bone re-modelling. (Kistner et al., 2022)
CRP, another commonly used inflammatory marker also has other normal functions. CRP exists in two isoforms. In its monomeric form (mCRP) it acts as a chemoattractant and is generated at the site of injury, which is at the core of classical inflammation. CRP in its pentameric form (pCRP) is involved in wound healing, clearance of damaged cells, and tissue regeneration. This can be considered a legitimate part of inflammation. However, tissue repair and maintenance is also a normal process that continues in the absence of any injury or infection trigger and it is suggested that pCRP is produced for this purpose even without inflammation. Giudice & Gangestad, (2018) argue that moderately elevated levels of IL-6 and CRP can occur in the complete absence of inflammation and tend to have anti-inflammatory effects.

V. A Fundamental Question: Does Elevated Level of an Inflammation Associated Molecule Necessarily Reflect Elevated Inflammation Activity?

To understand how inflammation works, it is important to understand the principle behind how immune cells aggregate at site of injury. Here, gradient is the key. The chemo-attractants act as signaling molecules that form concentration differences in the body. The concentration differences lead to formation of gradients. The strength of such a gradient depends upon the level of the chemoattractant molecules at the site of injury (local level) and the basal systemic level. The gradient allows the immune cells to migrate to the appropriate location. When the basal levels rise, the gradient weakens. Therefore, it is likely that higher levels of some of the inflammatory markers tend to decrease rather than increase the inflammatory response. It might be misleading therefore to assume that a higher level of a molecule involved in cell migration response always indicates higher inflammatory response (Watve & Mandani, 2008).
Innate immunity is a “spatiotemporal” process. Cells migrate based on different signals. The relative concentrations of molecules at different locations may be more important than the absolute ones. The same molecule may have different effects based upon where it is secreted, what are its relative levels at different locations, which other signals accompany it and which cell and receptors it interacts with. The downstream pathways of cell surface receptors and soluble receptor molecules can be very different (Diao et al., 2021; Mai et al., 2009; Osma-Garcia et al., 2016; Yuki, n.d.). Therefore, inferring anything from the raised levels of one or a few molecules can be misleading. For the same reason, classifying molecules into pro- versus anti-inflammatory is too simple to be true and useful. Many molecules have been claimed as both pro and anti-inflammatory in different contexts. All these are high alarms against the misuse of one or a few molecules as inflammatory markers.

VI. Potential Absurdities/ Anomalies that Need Critical Re-Examination

Systemic inflammation: Systemic inflammation is characterized by the heightened levels of certain inflammatory mediators, like cytokines, chemokines, and acute phase proteins like CRP. It is said to be a whole-body inflammation response. The cellular process of inflammation comprises aggregation of immune cells. Aggregation is a locale specific process and it is absurd to say that they aggregate everywhere. Clearly the concept of systemic inflammation is not compatible with the classical cell aggregation based definition. If the working definition of systemic inflammation is based on one or a few markers, it can be misleading as argued earlier. If it is about activation of immune mechanisms, one would expect that the system would be ready to launch a quicker response to injury/infection leading to rapid recovery. But in contrast, in the disorders like diabetes characterized by systemic inflammation, wound healing is typically delayed or impaired (Marjana Tomic-Canic & Luisa A. DiPietro, 2019; Wilkinson et al., 2019) and the frequency and severity of cutaneous infections is higher (Prado et al., 2023; Ren et al., 2026). This is not compatible with the classical perception of inflammation as an immune mechanism.
Inflammaging: With age the level of systemic inflammation is said to go up and that is assumed to be central to the age-related decline in body functions and health, a phenomenon called inflammaging. A serious problem with this argument is that the association between aging and inflammatory markers is not consistent across human communities. The data behind inflammaging comes mainly from the Western, educated, industrialized, rich, and democratic (WEIRD) societies. However, only 11% of the world’s population lives in these societies. Hence, WEIRD societies are not necessarily a good model for studying inflammation. The Filipino and Shuar communities showed low levels of aging associated CRP than the WEIRD societies. McDade, (2023) states that prenatal nutrition, microbial exposure in early life, breastfeeding durations and overall early developmental factors are crucial in deciding the age-inflammation association. The evidence suggests that adults with early exposure to richer microbial environments, show low levels of baseline CRP compared to those raised in sanitized western settings. As a result, one can conclude that different communities show a distinctly different pattern, hence one must also not assume that inflammation increases with age, and concepts such as “inflammaging” need to be re-examined (McDade, 2023).
Is this inflammation? Without any explicit definition, the word inflammation is being used for anything that the so called “immune cells” do. For example, the role that macrophages play in embryo implantation has also been called inflammation (Mezu-Ndubuisi & Maheshwari, 2021; Park et al., 2025; Sharma et al., 2025). The ambiguity as to whether the response of these cells to defence related triggers is to be called inflammation or anything that these cells do will be called inflammation needs to be resolved first. In the case of the latter, even embryonic development, metabolism and normal tissue homeostasis will have to be called inflammation. This means that right from zygote formation to death, the body is in a continuous state of inflammation. This makes terms like the “inflammatory response” meaningless. If the behaviour of these cells above normal is to be called inflammation, the distinction between normal and triggered responses needs to be clarified first.
The cause-effect confusion: Macrophages play a role in lipid metabolism and the formation and maintenance of adipose tissue (Jang et al., 2025). Thus, there is an association between adipose tissue and macrophages. Does this mean that adipose tissue “causes” inflammation? It is necessary to look at this and many other associations critically for cause-effect relationships so as to avoid misinterpretations.
The Good-bad connotation: Almost throughout the literature on chronic inflammation, the word is used with negative connotation. Is chronic inflammation always bad? If so, how did it survive the selective forces during evolution? The evolutionary underpinnings of physiology and pathophysiology are yet very superficially understood. Everything that we theorize in this field needs to withstand robust evolutionary analysis. Evolutionary medicine is no more a speculative field, it is rapidly becoming a robust, testable and applicable foundation of all our understanding of physiology and medicine (Watve & Diwekar-Joshi, 2016). If any mechanism of the body is harmful to itself, the question why it remained evolutionarily stable needs to be addressed critically and systematically. Any evolutionary hypothesis needs to be backed by sound evolutionary principles, make differential testable predictions and contribute novel insights to our understanding of health and disease (Watve & Diwekar-Joshi, 2016). Handwaving arguments are no more acceptable in evolutionary medicine. The immune system being highly complex, insights into its evolution have started emerging only recently (Bolnick et al., 2025) but many aspects remain unaddressed even now.

VII. An Evolutionary Interpretation of “Low Grade Chronic Systemic Inflammation”

One of the principles of evolutionary medicine is the mismatch hypothesis (Watve, 2013). The mechanisms of our body evolved for a set of ecological challenges faced by the ancestors and are optimized for it. But today’s lifestyle is substantially different than what we evolved for. It is possible that a system that was adaptive in one context can turn maladaptive in a mismatched context. Mainstream evolutionary medicine has discussed a limited range of mismatches such as the dietary mismatch and the flight or fight response. There are more mismatches whose potential effects have not been appreciated so far.
During ancestral life, the frequency of minor injuries was presumably much higher. The most common trigger for small but acute inflammatory response would have been small pricks, bruises, scratches, cuts and insect bites/stings. This would have been the most frequent challenge of innate immunity. Although it sounds minor and has been largely ignored by immunological thinking, any minor injury can potentially get infected and therefore this component of innate immunity is extremely important. In contrast to frequent minor injuries of ancestral life, urban life today is characterized by all-time cushioned surroundings and sedentary habits. The frequent minor injury stimuli for which the innate immune system evolved has become extremely rare. As a result, normal dynamics of immune cells is bound to have altered.
Considering the normal dynamic of immune cells, with every small cutaneous injury trigger, a small population of granulocytes and monocyte-macrophages will leave the blood stream and migrate to the site of injury. Although individual injuries would be minor, the high frequency of such small triggers implies a considerable continued movement of immune cells from blood vessels towards the cutaneous and subcutaneous tissue. Granulocytes and circulating monocytes originate from the bone marrow and circulate through the bloodstream. They migrate to the site of every injury guided by the gradient of chemo-attractants secreted at the site of injury. This is the fundamental process of acute inflammation. At the site of injury these cells use a series of means including phagocytosis and reactive oxygen species (ROS) generation to kill invading germs and prevent infection. The inflammatory response is normally accompanied and followed by enhanced lymphatic drainage, removal of immune cells participating in phagocytosis, antioxidant mechanisms, tissue repair and angiogenesis. The healing process involves a set of growth factors and many growth factor expressions are stimulated by minor injuries. What is more interesting to note is that even anticipation of injuries stimulates some of these mechanisms (Aloe et al., 1994; Watve, 2013). Many of the growth factors involved in wound healing are secreted by the salivary glands following behaviors such as aggression (Byyny et al., 1974; Lakshmanan, 1986; NEXØ et al., 1981; Noguchi et al., 1990) that increase the probability of injury. Salivary glands is the appropriate site for expression (Aloe et al., 1994) because animals lick wounds and thereby supply the required growth factors directly.
On this background what do we expect to happen with modern lifestyle that is not only deficient in minor injuries but also in events of anticipation of injuries? The rate of turnover of immune cells is expected to reduce in the modern sedentary lifestyle. In the absence of peripheral injury stimuli extravasation of immune cells will be slow and so would be the lymphatic drainage. Rapid clearing of chemo-attractants by lymphatic drainage is important for a sharper gradient guiding the cell migration. If more of the chemokines diffuse randomly and not quickly removed by lymphatic drainage, the gradient will be weaker reducing the cell migration further. Since phagocytic activity followed by clearance of effete cells also goes down, we expect greater accumulation of senescent cells in the subcutaneous tissue. When senescent cells accumulate, but fresh macrophages are not being recruited at a normal rate, it becomes an autocatalytic vicious cycle. Too many senescent cells accumulating and their signals unable to generate a sharp gradient because of subnormal lymphatic clearance can lead to accumulation of the signals which reduces further recruitment rather than enhancing it, leading to the phenomenon of senescence-associated secretory phenotype (SASP) (Alqahtani et al., 2025; Lopes-Paciencia et al., 2019; Saito et al., 2024; B. Wang et al., 2024). The signals given by senescent cells including interleukins, chemokines, cytokines, proteases, growth factors that are supposed to facilitate clearance of senescent cells are counterproductive because of the inability to form clear gradients. This has been demonstrated in studies showing that multiple cell types in the diabetic wounds are senescent (Marjana Tomic-Canic & Luisa A. DiPietro, 2019).
This can simply be the direct result of abnormally infrequent injury stimuli alone or it could be because of additional mechanisms. There is likely to be another mechanism evolved to optimize the investment in innate immunity. Investment trade-off is a known principle in evolution. Some trade-off between peripheral versus systemic immunity is shown in experimental challenges in invertebrates (Seal et al., 2026). The peripheral versus central immunity tradeoff is visualized in humans too in an evolutionary perspective (West-Eberhard, 2019). As the modern lifestyle is deficient in peripheral injuries on the one hand, it is likely to be accompanied by more frequent contagious diseases due to crowding. Therefore, disinvesting from peripheral immunity to support systemic immunity is a plausible response of the immune system to modern lifestyle. A simple way to achieve this is to further weaken the chemoattractant gradient generated from any cutaneous injury. That can be done by increasing the basal levels of some of the chemo-attractants (Watve & Mandani, 2008). Since the gradient is because of the difference between local and basal levels of chemo-attractants, increasing basal levels would decrease rather than increase cell migration. This is achieved by expression of the chemokines by central organs such as visceral fat or kidney. The raised levels of circulating pCRP may also reduce granulocyte migration (Bennett et al., 2018; Heuertz et al., 1999; Nagasawa, 2026; Olson et al., 2023). Arguably this small investment in basal levels of chemo-attractants can save a greater cost of immune cell migration to sites where they are least likely to be needed (Watve & Mandani, 2008).
The link with obesity and the so-called systemic inflammation is also likely to have evolved for optimizing immune response. Foraging behavior is optimized by finding the best trade-off between nutritional gains and foraging risk. At molecular level, this optimization is brought about by the interplay between leptin (a signal of stored energy) and cocaine- and amphetamine-regulated transcript (CART), a signal of foraging risk (Baig et al 2019). When there is enough of stored fat, the foraging drive becomes weaker, particularly if foraging is risky. Foraging increases the chances of injury. When foraging becomes unnecessary owing to stored fat, it makes sense to reduce the investment from peripheral innate immunity. When stored energy is minimal, foraging is necessary in spite of risk and this is where investing more in peripheral immunity is necessary. It would be most appropriate that the signals for this innate immunity transition are given by adipose tissue itself. This transition needs to be sufficiently quick and plastic to be adaptive. However, if fat store remains chronically high, as with the modern-day obesity, the plasticity may deteriorate (Bilal et al., 2026; Hou et al., 2011; Kistner et al., 2022).
Our synthesis necessitates a rethinking of the word systemic inflammation. If the main hallmarks of inflammation namely cell migration under chemoattractant gradient, phagocytosis, facilitated lymphatic turn over, and triggering the follow up healing cascades are all impaired or downregulated, calling it inflammation is absurd. What we call chronic systemic inflammation today is not a type of inflammation but actually a deficiency of the normal frequency of acute inflammations. The condition can easily be reversed by reversing the sedentary and injury free lifestyle. In deficiency diseases, supplementing what was deficient is the best remedy and no other drug can give comparable relief. Here physically active life with more or less normal injury and injury anticipation stimuli is the best remedy. Since the condition is not driven by an inflammation at all, anti-inflammatory treatments will at its best show marginal superficial difference and would not be able to reverse any of the conditions.
Currently since the popular perception is that chronic inflammation is damaging, the pathology of diabetes, cardiovascular disease, kidney disease and many types of neuronal disorders are said to be caused by chronic inflammation. If we reject the notion that chronic systemic inflammation is inflammation at all, alternative causes for the pathology would have to be sought. This, in fact, is likely to bring more clarity to the pathophysiology of these disorders and lead to more insightful approaches to treatments. We have already said that growth factor expressions are behavior responsive and the deficiency of the hunter gatherer behaviors for which our body is optimized characterizes modern lifestyle. Growth factors are expressed by every injury and are important and essential mediators in the healing process too (Chandra et al., 2026). The deficiency of the behaviors as well as of frequent minor injuries is bound to alter the growth factor dynamics. Since growth factors are involved in stem cell maintenance, angiogenesis, neuro-protection and metabolism among other functions, a cascade of changes can follow altered growth factor expression. Growth factors are critical for angiogenesis, revascularization and endothelial function. Endothelial dysfunction is the underlying cause of multiple disorders (Ackermann, 2017; Dzau & Gibbons, 1991). The deficiency of a set of behaviors to which our physiology has been optimized is likely to be directly responsible for the pathological changes independent of inflammation (Watve, 2013).
Based on this concept a set of alternative pathophysiological hypotheses for different lifestyle related disorders which need to be tested with a differential prediction approach (Watve & Keskar-Sardeshmukh, 2024). It is very likely that giving up the chronic inflammation narrative will facilitate research on alternative possibilities of the true pathophysiological mechanisms of life style related disorders.
If the hypothesis of deficiency of minor injuries and injury anticipating behaviors is true, we expect a number of outcomes. Some of these testable predictions are already known to be true. It is possible to subject them further to more specific tests.
(i) By this hypothesis diabetics and others affected by lifestyle related disorders should be much more susceptible to cutaneous infections and non-healing wounds as compared to respiratory and other systemic infections (Marjana Tomic-Canic & Luisa A. DiPietro, 2019; Prado et al., 2023; Ren et al., 2026; Wilkinson et al., 2019).
(ii) Impaired would healing is the most obvious prediction of our hypothesis. In contrast it is not a straightforward logical prediction of the systemic inflammation hypothesis. If the altered rate of migration of immune cells is a major cause of wound healing problems, enhancing the migration would facilitate wound healing which has been demonstrated. Exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the influx of macrophages and neutrophils, followed by an increase in interleukin-6 and monocyte chemoattractant protein-1 production resulting into increase in neovascularization and stimulated wound healing (Fang et al., 2010; Yo et al., n.d.). In addition, injuries and injury anticipating behaviors directly trigger a series of growth factors. Growth factors play a role in M1 to M2 transition as well as other processes in wound healing including neovascularization, epithelial cell growth and wound closure (Nishikoba et al., 2020; Yaseen & Khamaisi, 2020; Zhang et al., 2017). We expect therefore that when the behavior stimuli are normal, wound healing will be normal.
(iii) Our hypothesis expects that adipose tissue is one of the mediators of behavior transition and thereby the immunity transition. Therefore, obesity and related disorders would be correlated negatively with the mechanisms of peripheral immunity and cutaneous wound healing.
(iv) Evidence suggests that the lymphatic drainage system is crucial for the clearance of acute inflammatory response, removal of cytokines, catabolic factors and inflammatory cells from the site of injury/stimulus and other mediators of inflammation in rheumatoid arthritis (Bouta et al., 2018), post myocardial infarction (Vieira et al., 2018), and even the clearance of lipoproteins from inflamed atherosclerotic tissue (Yeo et al., 2021). As expected by our hypothesis, lifestyle related disorders are strongly associated with lymphatic dysfunction, which leads to decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells (Galkowska et al., n.d.; Hespe et al., 2016)
(v) If reduced minor injury stimuli are responsible for the altered inflammatory state, increasing such stimuli would reverse the conditions. This is shown to happen by acupuncture and acupressure treatments (Li et al., 2021; Lin et al., 2015; Oh & Kim, 2022). It is well-known that acupuncture treatments have substantial “anti-inflammatory” effects (Li et al., 2021). Some of the studies show that even “sham” acupuncture i.e. stimulating the skin randomly independent of specific acupoints is also effective in ameliorating systemic “inflammation” which is compatible with our hypothesis (Kaptchuk, 2020; Musial, 2019; Näslund et al., 2011).
(vi) Exercise partially reverses the sedentary lifestyle but it is also likely to induce the injury anticipation response. Behaviorally enriched exercises or active sports which mimics many hunter-gatherer behaviors such as chasing and catching something, aiming at something, attacking or defending something are expected to supplement the injury anticipation responses and thereby expected to reverse the innate immunity changes. Although there are no specific tests of behaviorally enriched exercises, exercises in general are known to resolve the condition. In obesity-related settings, aerobic exercise was found to decrease peri-lymphatic inflammatory cell accumulation, improve lymphatic function and reverse pathological changes in gene expression in lymphatic endothelial cells, which was independent of weight loss. (Hespe et al., 2016). In case of diabetic wound healing, exercise significantly increased angiogenesis, inhibited M1 macrophage infiltration and increased M2 macrophage count which significantly accelerated the wound healing process (Kawanishi et al., 2022).
(vii) The classically perceived role of exercise is that it burns calories and improves the energy balance, thereby reducing fat. The adipose tissue is said to mediate the systemic inflammation (Adolph et al., 2017; Chait & den Hartigh, 2020). An important prediction differentiating this perspective from our perspective is that by our hypothesis exercise benefits should be seen independent of weight loss. Wherever differentially tested, the advantages of exercise were found to be faster and independent of weight or fat loss (Hespe et al., 2016; Kawanishi et al., 2022). Although the adipose tissue is likely to be one of the mediators of the immune transition, there would be mechanisms that work independent of adiposity. A further testable prediction of our hypothesis is that for equal calorific requirement, behaviour enriched exercises will be more effective than mechanistic exercises.
Since, in the lifestyle associated set of disorders, apart from fractional and inconsistent prevention of complications the success of treatment is extremely limited (Adigbli et al., 2024; Boussageon et al., 2017; Group, 2008; Investigators, 2009; Lee et al., 2021; Natale et al., 2023; Ojha et al., 2023; Watve et al, 2024) , we need to cross question the prevalent theories. It is likely that the limited effectiveness of treatments is because of a lack of clear perception of the true pathophysiology. Cross questioning the concept of chronic systemic inflammation is a small part of the bigger picture. Along with that we should also be open to alternative interpretation that can be tested using a model prediction matrix (Ojha & Watve, 2024) and testing the predictions eventually.

VIII. Conclusions

  • At present there is too much conflation of mutually contradicting ideas in the concept of inflammation. There is a need to redefine inflammation with clear delimitations. The definition needs to be limited to innate immune response to triggers by injury or infection. Ill-perceived triggers such as autoimmunity or hypersensitivity should be included. All immune cells have a diversity of normal physiological functions other than immunity. Similarly, the signal molecules involved in inflammation have a diversity of functions other than inflammation. These normal physiological functions of the so-called immune cells and the so-called inflammatory markers should be excluded from the definition of inflammation. For example, the role of macrophages in embryo implantation need not be called inflammation.
  • Relying on the altered levels of one or a few “inflammatory markers” as a working definition of inflammation can be misleading and needs to be given up. The word inflammation needs to be restricted to appropriate cell migration and aggregation responses under a clearly demonstrated defense related context.
  • Complete rethinking of the so called “low grade chronic systemic inflammation” condition is required. It is ironic to call a condition as inflammation when the classical inflammation hallmarks are actually impaired or downregulated. We need to reinterpret the so-called systemic inflammation with a set of alternative possible interpretations, churn out their differential testable predictions and take an empirical approach to test and support or reject the alternatives so as to arrive at a sound interpretation.
  • More precise definitions, and a critical approach to cause-effect clarity is likely to clear many ambiguous generalizations and pave the way for better insights into lifestyle related disorders and their prevention as well as reversal.

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