Biological Divergence Influences Signalling Responses
Neuronal Cytokine Sensing
EPIGENETICSEXPOSOMEIMMUNOLOGYPHARMACOLOGY
Alexandra Chambers
8/27/20265 min read
The immune system and nervous system are closely connected and they constantly send information to each other. Neurons, the cells that carry information through the nervous system, can directly detect immune signals called cytokines. Cytokines are small molecules released by cells to communicate with other cells. When neurons detect them, their activity can change. Researchers have described this two-way communication network as a neuroimmune connectome. Cytokine signalling is involved in development, maintaining biological stability and responding to infection or injury. When these signals continue for too long or become poorly regulated, they can also contribute to problems with neuronal function.
This changes how we can think about neuroinflammation. Neurons are not simply sitting inside an inflamed environment while immune cells act around them. They can receive and respond to immune information themselves. Cytokines can change how neurons communicate with one another, how strong their connections are, how many connections they form and how larger brain networks behave. Interferons, which are a family of cytokines, can also change which genes are switched on or off inside neurons and influence how developing neurons grow. This means that the effect of inflammation depends partly on the signal being produced and partly on how the cells receiving that signal respond to it.
Immune signals can even change neuronal network activity. Malorny et al. (2026) studied slices of rat hippocampal tissue and exposed them to the inflammatory cytokine TNF-α. Longer exposure changed the electrical activity of neuronal networks, including brain-wave activity known as gamma oscillations, and caused periods of increased electrical excitability. When TNF-α and IFN-γ were used together, the effects became more severe. The neuronal networks demonstrated abnormal bursts of electrical activity and, under some conditions, stopped producing electrical activity altogether. Oxidative stress, metabolic stress and nitric oxide produced by microglia were involved. Short exposure to TNF-α did not produce the same effects. The important point is that the same biological signal can have different effects depending on how long it is present and what else is happening in the surrounding system.
Communication can also travel back in the opposite direction. Hashimoto et al. (2026) identified neurons that responded to the inflammatory cytokine IL-1β. When researchers later activated those neurons experimentally, the animals developed several features associated with inflammation, including increased IL-6, increased corticosterone and a faster heart rate. The researchers traced this response through a specific pathway in the brain. This shows that an immune signal can change neural activity and that neural activity can then influence inflammation, hormones and cardiovascular function. The immune and nervous systems are therefore part of an interacting feedback network rather than a simple one-way chain.
Neurons can also detect biological signals earlier in the immune response. Neurons and glial cells contain systems that recognise RNA and DNA. These systems help cells detect infection and can trigger interferons and other inflammatory signals. They can also respond to RNA or DNA originating from the body's own cells under some circumstances. The same sensing pathways are involved in brain development and neuronal function. When their activity becomes dysregulated, however, they can contribute to inflammation within the nervous system and to neuronal degeneration.
This is where our Divergent Genomics framework becomes important. The same exposure(s) cannot be expected to produce exactly the same biological response in every person because the biology receiving that exposure is different. We can think about this in three stages: signal production, signal persistence and signal interpretation. First, people may produce different amounts or combinations of immune signals after the same trigger. Second, those signals may disappear quickly in one person but continue for longer in another. Third, the cells receiving those signals may respond differently. Genetic variation can influence receptors on the cell surface, which genes become active and how signalling pathways such as interferon responses operate. These differences can then influence the cellular response that follows.
There is already experimental evidence for this. Andzelm et al. (2025) created neurons from cells donated by more than 100 genetically different people. The researchers exposed those neurons to the interferons IFN-α and IFN-γ. They found hundreds of genetic differences linked to differences in how genes responded to the interferons. Some of those genetic effects only became visible after interferon exposure. The study is currently a preprint awaiting peer review, but it demonstrates a very important principle: neurons from genetically different people can respond differently to the same immune signals.
Timing is significant too, particularly during early (neuro)development. Research using developing human neurons has shown that temporary exposure to IFN-γ can alter the growth of neurites, the extensions that eventually help neurons connect with other cells. It can also produce changes in immune-related proteins and signalling pathways inside developing neurons. Other experiments have found changes involving STAT1, HLA-B, C4A and synapsin proteins following IFN-γ exposure. This means that a biological signal arriving during (neuro)development can interact with the genomic characteristics of the developing cell and influence what happens next.
Therefore, a biological signal does not act in isolation - its effect depends on the biological system receiving it. The amount of a cytokine is also important and how long it remains. The developmental stage of the cell and the surrounding biological environment is also relevant. Genetics can also influence how the signal is detected, processed and translated into cellular activity. This means that biological outcomes emerge from the interaction between the signal and the receiver. Two people can encounter the same exposure(s) without experiencing the same biological event because their cells may produce, clear and interpret the resulting signals differently. Human biological diversity exists not only in our genes, but in the way those genes influence how our cells respond to the world around them.
These findings also have important pharmacological and pharmacogenomic implications. Medicines and other biological interventions are usually administered as standardised exposures, but the response to that exposure occurs within a genetically and biologically variable system. If genetic variation can alter how neurons respond to cytokines and interferons, then interventions that generate, suppress or modify those signalling pathways do not produce biologically equivalent effects in every person. The same dose or exposure can therefore lead to different downstream signalling, different durations of response and potentially different physiological consequences. This becomes particularly important when an intervention deliberately activates the immune system, because the biological effect depends not only on what is administered, but on how the individual receiving it produces, regulates and interprets the resulting signals. From a Divergent Genomics perspective, pharmacological exposure and biological response are therefore not interchangeable concepts.
References
Andzelm, M.M., Bolshakova, S., Pettinari, N., Tegtmeyer, M., Meyer, D., Johnson, A. et al. (2025) ‘Human genetic variation shapes the response of neurons to interferons’, bioRxiv. Preprint. Available at: https://doi.org/10.1101/2025.05.28.653507
Hashimoto, O., Hepler, T.D., Tynan, A., Torres, A., Li, J.H., Brines, M. et al. (2026) ‘Central neurons encode interleukin-1β signals and mediate stress-induced inflammation’, Journal of Experimental Medicine, 223(4), e20252000. Available at: https://doi.org/10.1084/jem.20252000
Malorny, N., Chausse, B., Khodaie, B., Elgez, A., Söder, L., Lewen, A. et al. (2026) ‘TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress’, Journal of Neuroinflammation, 23(1), 160. Available at: https://doi.org/10.1186/s12974-026-03835-x
Image: Nicolas-Henri Jacob, neuroanatomical lithograph from Jean-Baptiste Marc Bourgery’s Traité complet de l’anatomie de l’homme, c. 1844. Public domain. Source: Wikimedia Commons.