Homeostasis, Inflammation, and Disease Susceptibility
Open accessAbstract
While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension, and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue, and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation.
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Chronic low-grade inflammation in the kidneys impairs normal repair mechanisms after injury and promotes immunosenescence and organ damage.
“Chronic low-grade inflammation in the kidneys can impair the normal repair mechanisms that occur following injury. This inflammation hampers intrinsic cellular repair mechanisms following injury and promotes immunosenescence and organ damage.151,152”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [151]
The 'Inflammation and homeostatic circuits' section says persistent inflammation can disrupt homeostatic controls and contribute to chronic pathological states. It does not establish that low-grade inflammation in the kidneys impairs repair after injury or promotes immunosenescence and organ damage; searches for kidney, immunosenescence, and repair after injury did not find those links. Page numbers were unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredInflammation is an evolutionarily conserved process that activates immune and non-immune cells to protect the host from pathogens and promote tissue repair.
“Inflammation is an evolutionarily conserved process characterized by the activation of immune and non-immune cells that protect the host from bacteria, viruses, toxins and infections by eliminating pathogens and promoting tissue repair and recovery2,9.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [9]
Depending on the inflammatory response, metabolic and neuroendocrine changes can occur to conserve energy and direct nutrients to the activated immune system.
“Depending on the degree and extent of the inflammatory response, including whether it is systemic or local, metabolic and neuroendocrine changes can occur to conserve metabolic energy and allocate more nutrients to the activated immune system9–12.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [9]
A shift from short-lived to long-lived inflammation can break immune tolerance and alter tissues, organs, and cellular physiology, raising the risk of non-communicable diseases in both young and older people.
“Shifts in the inflammatory response from short- to long-lived can cause a breakdown of immune tolerance9,15 and lead to major alterations in all tissues and organs, as well as normal cellular physiology, which can increase the risk for various non-communicable diseases in both young and older individuals1,9–11,15,17–21.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [9]
A normal inflammatory response is temporally restricted, upregulating inflammatory activity when a threat is present and resolving after the threat passes.
“A normal inflammatory response is characterized by the temporally restricted upregulation of inflammatory activity that occurs when a threat is present and that resolves once the threat has passed9,13,15.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [9]
Systemic chronic inflammation is low-grade and persistent and causes collateral damage to tissues and organs over time, including oxidative stress.
“SCI is low-grade and persistent (as the name suggests) and ultimately causes collateral damage to tissues and organs over time, such as by inducing oxidative stress1,4,9,19.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [9]
Chronic systemic inflammation is associated with aging, is low-grade and persistent, and ultimately causes collateral damage to tissues and organs.
“This type of inflammation is associated with aging and is characterized by being low-grade and persistent, ultimately leading to collateral damage to tissues and organs1,17.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [1]
Inflammatory components of the immune system are often chronically elevated in older people and are linked to higher incidence of cancer, cardiovascular disease, neurodegenerative disorders and other conditions.
“inflammatory components of the immune system are often chronically elevated in aged individuals and associated with an increased incidence of cancer, cardiovascular disease, neurodegenerative disorders and others1–3”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [1]
In both NAFLD and cholestasis, failed or inadequate metabolic adaptation to substrate overload results in sublethal cell stress or cell death with release of mediators and extracellular vesicles driving inflammation and fibrosis.
“In both scenarios failed or inadequate metabolic adaptation to substrate overload results in sublethal cell stress or even cell death with release of mediators and extracellular vesicles driving inflammation and fibrosis15–17”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [15]
Inflammation is theorized to be a unifying feature of homeostatic perturbation, providing a protective response to extreme deviations from the homeostatic set point.
“Inflammation is theorized to be a unifying feature of homeostatic perturbation: providing a protective response to extreme deviations from the homeostatic set point174,175.”
From Neural mechanisms of social homeostasis (2019) · cites this paper as [175]
Some resistance mechanisms, including those involved in nutritional immunity, can compromise host homeostasis, and this trade-off is countered by tissue damage control, which confers disease tolerance to infection.
“While essential to confer host protection against infection, some resistance mechanisms, including those involved in nutritional immunity, can compromise host homeostasis [10].This trade-off is countered by an additional host defense strategy termed as tissue damage control [1,11], which confers disease tolerance to infection [1,12,13].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [10]
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- Authors
- Kotas, M. E., & Medzhitov, R.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Medzhitov, Ruslan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 816-827
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4369762
- OpenAlex
- W2120049814
- Cited by
- 1,213
- References
- 71
- Citations by year
- 2026: 90 · 2025: 124 · 2024: 118 · 2023: 145 · 2022: 150 · 2021: 137 · 2020: 101 · 2019: 110 · 2018: 78 · 2017: 68 · 2016: 63 · 2015: 26
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000142)
- National Cancer Institute (R01CA157461, CA157461)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Allergy and Infectious Diseases (AI089771, R01AI089771, R37AI046688, AI046688, R01AI046688)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK071754, R01DK071754)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- homeostasis, chronic inflammation, disease susceptibility, set point, dysregulation, obesity, hypertension, type 2 diabetes, chronic disease
- MeSH terms
- Diabetes Mellitus, Disease Susceptibility, Homeostasis, Humans, Inflammation, Models, Biological
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