Beyond Host Defense: Emerging Functions of the Immune System in Regulating Complex Tissue Physiology, Rankin & Artis, 2018

Indigophoton · Apr 22, 2018

The essential roles played by the immune system in the discrimination between self- versus non/altered-self and its integral role in promoting host defense against invading microbes and tumors have been extensively studied for many years. In these contexts, significant advances have been made in defining the molecular and cellular networks that orchestrate cell-cell communication to mediate host defense and pathogen expulsion. Notably, recent studies indicate that in addition to these classical immune functions, cells of the innate and adaptive immune system also sense complex tissue- and environment-derived signals, including those from the nervous system and the diet. In turn these responses regulate physiologic processes in multiple tissues throughout the body, including nervous system function, metabolic state, thermogenesis, and tissue repair. In this review we propose an integrated view of how the mammalian immune system senses and interacts with other complex organ systems to maintain tissue and whole-body homeostasis.
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Figure 1
Throughout Life, Organisms Are Exposed to a Wide Array of Factors That Multiple Tissues Must Respond to in Order to Maintain Homeostasis

Several recent studies have uncovered the contribution of the immune system in the regulation of not just pathogen expulsion but also other complex physiological processes, including neuron function in the central nervous system (CNS) and peripheral tissue, regulation of adipose tissue, and maintenance of metabolic and muscle tissue homeostasis. Dysregulation of the immune system in these tissues results in alteration in homeostasis and disease, such as obesity and neurological disorders. ASD, austism spectrum disorder; FAP, fibroadipogenic precursor; IBS, irritable bowel syndrome; WAT, white adipose tissue.
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It is becoming increasingly understood that dysregulation of the immune system results in diseases originally considered to be independent of the immune system, such as obesity, neurodegenerative disorders, and cognitive dysfunction. The function of the immune system is far more complex than previously appreciated. It works to regulate organismal homeostasis by sensing environmental and physiological perturbations, adapting to these alterations and re-establishing equilibrium in the host. It functions as a buffer to keep daily stresses in check and to ensure damage does not become irreversible, destroy tissue, and upset whole-body homeostasis.
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Here, we will describe recent advances in our understanding of how cytokine balance in the innate and adaptive immune systems is regulated by non-pathogenic signals, such as environmental- and neuronal-derived signals, and in turn how this cytokine balance regulates multi-organ homeostasis. Specifically, we will focus on recent findings that demonstrate how immune-derived signals regulate the neuronal circuitry, adipose tissue, and muscle function independent of pathogen challenge. We propose that recent advances in immunology research provide compelling evidence that the immune system functions as a multi-organ rheostat or buffer that, in absence of infection, continually senses homeostatic perturbations and relays signals to these tissues, thereby maintaining organismal homeostasis (see Figure 1).
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Figure 2
Regulation of Distinct Modules of the Immune Response

In the classically held view of the immune system, different types of pathogens can shift the equilibrium of the immune response for sufficient eradication of specific pathogens. For example, helminth infection promotes type 2 inflammation, whereas intracellular viral infection results in type 1 inflammation. However, other physiological stimuli can also skew the immune response toward type 1, type 2, or type 3 immunity. Cold exposure results in type 2 inflammation, whereas a diet rich in tryptophan results in production of AHR ligands and promotion of type 3 immunity. These changes in the immune response can then feed back to other non-immune tissues to regulate homeostasis and promote pathologies. Areg, amphregulin; AHR, aryl hydrocarbon receptor; cGRP, calcitonin gene-related peptide; EC, epithelial cells; FAP, fibroadipogenic precursor; NE, norepinephrine; NMU, neuromedin U; VIP, vasoactive intestinal peptide.
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Immune dysfunction and microbial dysbiosis are associated with neurological disorders and changes in behavior. The balance between the type 1, type 2, and type 3 cytokine milieu alters the homeostatic set point of the central nervous system (CNS), thereby affecting neuronal function and behavior (see Figures 1 and 2). Preserving homeostasis of the CNS and neurological function is important for organism survival because these pathways regulate behaviors, such as feeding, energy expenditure, mating, and protection from predators. Neuro-physiological homeostasis in the CNS results from the careful crosstalk between neurons and its supporting glial cells, and perturbations in these pathways lead to behavioral changes and disorders, such as autism spectrum disorder (ASD), dementia, and schizophrenia.

The best-characterized behavior regulated by the immune system is sickness behavior, exhibited by all mammals during infection. Sickness behavior presents with anorexia, reduced libido, lethargy, and social withdrawal, behavioral changes that are thought to occur to reduce the risk of spreading infection and allow the body to rest and recover. Pro-inflammatory cytokines produced in response to inflammation by the innate immune system, namely tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, and IL-18 can act on neuronal circuits to cause sickness behaviors such as anorexia and cognitive impairment
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http://www.cell.com/cell/fulltext/S0092-8674(18)30293-9

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Beyond Host Defense: Emerging Functions of the Immune System in Regulating Complex Tissue Physiology, Rankin & Artis, 2018

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