NEURO-ENDOCRINE-IMMUNE CROSSTALK IN CHRONIC DISEASES: AN INTEGRATIVE REVIEW OF MOLECULAR MECHANISMS, BIOMARKERS, AND PREVENTIVE STRATEGIES

Authors

DOI:

https://doi.org/10.31435/ijitss.3(51).2026.6290

Keywords:

Policy development, School Management, Indiscipline, Leadership, Challenges and Strategies

Abstract

Background: The growing burden of chronic non-communicable diseases has highlighted the importance of the neuro-endocrine-immune (NEI) axis as a central regulatory network integrating neural, endocrine, and immune signaling to maintain physiological homeostasis and coordinate adaptive responses to internal and environmental challenges. Increasing evidence indicates that disruption of this bidirectional communication contributes to chronic low-grade inflammation, impaired stress adaptation, and the development of multiple chronic diseases.

Objective: This integrative review aims to synthesize current evidence on the molecular mechanisms, regulatory networks, biomarkers, and translational implications of neuro-endocrine-immune crosstalk, with particular emphasis on its relevance for preventive strategies and personalized medicine.

Materials and Methods: An integrative review of peer-reviewed literature indexed in PubMed, Scopus, and Web of Science was conducted. The available evidence was synthesized to identify key molecular pathways, neuroimmune regulatory mechanisms, environmental sensing pathways, and clinically relevant biomarkers associated with neuro-endocrine-immune (NEI) dysregulation.

Results: The available evidence indicates that disruption of NEI crosstalk promotes persistent inflammatory activation, autonomic imbalance, impaired glucocorticoid signaling, and immune dysregulation, thereby contributing to the initiation and progression of major chronic diseases. Inflammatory mediators, cortisol dynamics, autonomic indices, microbiota-derived metabolites, and environmental sensing pathways have emerged as promising biomarkers and therapeutic targets for disease prevention and risk stratification.

Conclusions: The NEI axis represents a fundamental systems-level interface linking environmental exposures, stress responses, and chronic disease development. A deeper understanding of NEI crosstalk provides a scientific basis for identifying clinically relevant biomarkers and supports the development of predictive, preventive, personalized, and participatory strategies for chronic disease prevention and management.

References

Besedovsky, H. O., & del Rey, A. (1996). Immune-neuro-endocrine interactions: Facts and hypotheses. Endocrine Reviews, 17(1), 64–102. https://doi.org/10.1210/edrv-17-1-64

Tracey, K. J. (2002). The inflammatory reflex. Nature, 420(6917), 853–859. https://doi.org/10.1038/nature01321

Tracey, K. J. (2009). Reflex control of immunity. Nature Reviews Immunology, 9(6), 418–428. https://doi.org/10.1038/nri2566

Kipnis, J. (2016). Multifaceted interactions between adaptive immunity and the central nervous system. Science, 353(6301), 766–771. https://doi.org/10.1126/science.aag2638

Pavlov, V. A., & Tracey, K. J. (2017). Neural regulation of immunity: Molecular mechanisms and clinical translation. Nature Neuroscience, 20(2), 156–166. https://doi.org/10.1038/nn.4477

Dantzer, R. (2018). Neuroimmune interactions: From the brain to the immune system and vice versa. Physiological Reviews, 98(1), 477–504. https://doi.org/10.1152/physrev.00039.2016

Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56. https://doi.org/10.1038/nrn2297

Prinz, M., & Priller, J. (2014). Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease. Nature Reviews Neuroscience, 15(5), 300–312. https://doi.org/10.1038/nrn3722

Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., . . . Kummer, M. P. (2015). Neuroinflammation in Alzheimer's disease. The Lancet Neurology, 14(4), 388–405. https://doi.org/10.1016/S1474-4422(15)70016-5

Hansen, D. V., Hanson, J. E., & Sheng, M. (2018). Microglia in Alzheimer's disease. The Journal of Cell Biology, 217(2), 459–472. https://doi.org/10.1083/jcb.201709069

Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16(1), 22–34. https://doi.org/10.1038/nri.2015.5

Chrousos, G. P. (2009). Stress and disorders of the stress system. Nature Reviews Endocrinology, 5(7), 374–381. https://doi.org/10.1038/nrendo.2009.106

Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B. (2016). Regulation of the hypothalamic-pituitary-adrenocortical stress response. Comprehensive Physiology, 6(2), 603–621. https://doi.org/10.1002/cphy.c150015

Russell, G., & Lightman, S. (2019). The human stress response. Nature Reviews Endocrinology, 15(9), 525–534. https://doi.org/10.1038/s41574-019-0228-0

McEwen, B. S., & Akil, H. (2020). Revisiting the stress concept: Implications for affective disorders. The Journal of Neuroscience, 40(1), 12–21. https://doi.org/10.1523/JNEUROSCI.0733-19.2019

Slavich, G. M. (2020). Social safety theory: A biologically based evolutionary perspective on life stress, health, and behavior. Annual Review of Clinical Psychology, 16, 265–295. https://doi.org/10.1146/annurev-clinpsy-032816-045159

Hotamisligil, G. S. (2017). Inflammation, metaflammation and immunometabolic disorders. Nature, 542(7640), 177–185. https://doi.org/10.1038/nature21363

Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., Ferrucci, L., Gilroy, D. W., Fasano, A., Miller, G. W., Miller, A. H., Mantovani, A., Weyand, C. M., Barzilai, N., Goronzy, J. J., Rando, T. A., Effros, R. B., Lucia, A., Kleinstreuer, N., & Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. Nature Medicine, 25(12), 1822–1832. https://doi.org/10.1038/s41591-019-0675-0

Ridker, P. M. (2019). Anti-inflammatory therapy for atherosclerosis: Interpreting divergent results from the CANTOS and CIRT clinical trials. Journal of Internal Medicine, 285(5), 503–509. https://doi.org/10.1111/joim.12862

Libby, P. (2021). The changing landscape of atherosclerosis. Nature, 592(7855), 524–533. https://doi.org/10.1038/s41586-021-03392-8

Calder, P. C. (2022). Dietary factors and low-grade inflammation in relation to overweight and obesity revisited. The British Journal of Nutrition, 127(10), 1455–1457. https://doi.org/10.1017/S0007114522000782

Quintana, F. J. (2013). The aryl hydrocarbon receptor: A molecular pathway for the environmental control of the immune response. Immunology, 138(3), 183–189. https://doi.org/10.1111/imm.12046

Murray, I. A., & Perdew, G. H. (2020). How Ah receptor ligand specificity became important in understanding its physiological function. International Journal of Molecular Sciences, 21(24), 9614. https://doi.org/10.3390/ijms21249614

Yang, X., Liu, H., Ye, T., Duan, C., Lv, P., Wu, X., Liu, J., Jiang, K., Lu, H., Yang, H., Xia, D., Peng, E., Chen, Z., Tang, K., & Ye, Z. (2020). AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics, 10(26), 12011–12025. https://doi.org/10.7150/thno.51144

Ojo, E. S., & Tischkau, S. A. (2021). The role of AhR in the hallmarks of brain aging: Friend and foe. Cells, 10(10), 2729. https://doi.org/10.3390/cells10102729

Rejano-Gordillo, C. M., Marín-Díaz, B., Ordiales-Talavero, A., Merino, J. M., González-Rico, F. J., & Fernández-Salguero, P. M. (2022). From nucleus to organs: Insights of aryl hydrocarbon receptor molecular mechanisms. International Journal of Molecular Sciences, 23(23), 14919. https://doi.org/10.3390/ijms232314919

Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., & Pettersson, S. (2012). Host-gut microbiota metabolic interactions. Science, 336(6086), 1262–1267. https://doi.org/10.1126/science.1223813

Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., Guzzetta, K. E., Jaggar, M., Long-Smith, C. M., Lyte, J. M., Martin, J. A., Molinero-Perez, A., Moloney, G., Morelli, E., Morillas, E., . . . Dinan, T. G. (2019). The microbiota-gut-brain axis. Physiological Reviews, 99(4), 1877–2013. https://doi.org/10.1152/physrev.00018.2018

Ouyang, H., Yang, Y., Zhang, X., Cui, Y., & Zhang, Y. (2025). Microbial orchestration of neuroimmune crosstalk: From homeostasis to disease. Frontiers in Immunology, 16, 1679286. https://doi.org/10.3389/fimmu.2025.1679286

Gauthier, M. M., Hayoz, S., & Banek, C. T. (2023). Neuroimmune interplay in kidney health and disease: Role of renal nerves. Autonomic Neuroscience: Basic & Clinical, 250, 103133. https://doi.org/10.1016/j.autneu.2023.103133

Pu, T., Sun, J., Ren, G., & Li, H. (2025). Neuro-immune crosstalk in cancer: Mechanisms and therapeutic implications. Signal Transduction and Targeted Therapy, 10(1), 176. https://doi.org/10.1038/s41392-025-02241-8

Chang, L., Shan, J., Li, D., & Wang, X. (2025). Neuroendocrine-immune axis in endometriosis: A review on how the nervous system goes beyond pain perception. Biomolecules, 15(11), 1536. https://doi.org/10.3390/biom15111536

Panossian, A. G., Efferth, T., Shikov, A. N., Pozharitskaya, O. N., Kuchta, K., Mukherjee, P. K., Banerjee, S., Heinrich, M., Wu, W., Guo, D. A., & Wagner, H. (2021). Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress- and aging-related diseases. Medicinal Research Reviews, 41(1), 630–703. https://doi.org/10.1002/med.21743

Esmaealzadeh, N., Iranpanah, A., Sarris, J., & Rahimi, R. (2022). A literature review of the studies concerning selected plant-derived adaptogens and their general function in body with a focus on animal studies. Phytomedicine, 105, 154354. https://doi.org/10.1016/j.phymed.2022.154354

Panossian, A. (2023). Challenges in phytotherapy research. Frontiers in Pharmacology, 14, 1199516. https://doi.org/10.3389/fphar.2023.1199516

Hood, L., & Friend, S. H. (2011). Predictive, personalized, preventive, participatory (P4) cancer medicine. Nature Reviews Clinical Oncology, 8(3), 184–187. https://doi.org/10.1038/nrclinonc.2010.227

Hood, L., & Flores, M. (2012). A personal view on systems medicine and the emergence of proactive P4 medicine: Predictive, preventive, personalized and participatory. New Biotechnology, 29(6), 613–624. https://doi.org/10.1016/j.nbt.2012.03.004

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Published

2026-08-28

How to Cite

Turzyńska, P. P., Liedtke , M. M., Biskup, A. ., Wnęk , A., Martynowska, W. . ., Misiaszek, D. ., Grabowska, N. ., & Wolszczak, A. (2026). NEURO-ENDOCRINE-IMMUNE CROSSTALK IN CHRONIC DISEASES: AN INTEGRATIVE REVIEW OF MOLECULAR MECHANISMS, BIOMARKERS, AND PREVENTIVE STRATEGIES. International Journal of Innovative Technologies in Social Science, 2(3(51). https://doi.org/10.31435/ijitss.3(51).2026.6290

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