Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance
Open accessAbstract
Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.
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The mechanism underlying stress-induced worsening of end-organ function and death is likely a result of stress-induced IL6-dependent metabolic re-programming.
“The mechanism underlying this phenomenon is unclear, but likely is a result of stress-induced IL6-dependent metabolic re-programming similar to that which has been previously published by our group and others (Ganeshan et al., 2019; Luan et al., 2019; Wang et al., 2016; Wang A, 2019; Weis et al., 2017).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Ganeshan et al., 2019
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- Authors
- Ganeshan, K., Nikkanen, J., Man, K., Leong, Y. A., Sogawa, Y., Maschek, J. A., Van Ry, T., Chagwedera, D. N., Cox, J. E., & Chawla, A.
- Affiliations
- University of California, San Francisco (US)
- University of Utah (US)
- Corresponding author
- Chawla, Ajay
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 177
- Issue
- 2
- Pages
- 399-413.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6456449
- OpenAlex
- W2921819732
- Cited by
- 286
- References
- 58
- Citations by year
- 2026: 37 · 2025: 46 · 2024: 37 · 2023: 46 · 2022: 33 · 2021: 48 · 2020: 26 · 2019: 13
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (DK094641, DK101064, 1S10OD018210-01A1, 1S10OD021505-01)
- T32 (4 T32 HL 7731-25)
- EMBO (ALTF 1185-2017)
- NHMRC (GNT1121917, GNT1142229)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Physical Sciences › Environmental Science › Ecology › Physiological and biochemical adaptations
- Keywords
- energy trade-offs, hypometabolism, hypothermia, disease tolerance, immunity, homeothermy, TLR4, lipopolysaccharide, bacterial infection, energy conservation, tissue tolerance
- MeSH terms
- Animals, Body Temperature Regulation, Energy Metabolism, Female, Immune Tolerance, Immunity, Immunity, Innate, Male, Metabolism, Mice, Inbred C57BL, Mice
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