The Regulation of Immunological Processes by Peripheral Neurons

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The Regulation of Immunological Processes by Peripheral Neurons

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Title: The Regulation of Immunological Processes by Peripheral Neurons
Author: Ordovas-Montanes, Jose Manuel ORCID  0000-0001-5444-5601
Citation: Ordovas-Montanes, Jose Manuel. 2015. The Regulation of Immunological Processes by Peripheral Neurons. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: The nervous system and the immune system are the primary sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to stimuli with the appropriate valence and magnitude to optimize host fitness. Furthermore, an alluring parallel concept is that both systems have the capacity to form memories of these encounters leading to optimized and adaptive future responses. Recent work in the fields of neuroscience and immunology has led to a high-resolution map of cell subsets within both systems. Here, we start to leverage these advances to explore the relationship between these two sensory systems at the level of discrete cell subsets in immunological disease and homeostasis with a focus on interactions at barrier tissues. This work stems from the initial hypothesis that sensory neurons for noxious stimuli, nociceptors, regulate inflammation by controlling production of key instructive and effector cytokines derived from tissue-resident immune cells.
In our first investigation focused on the skin, we identified that NaV1.8+ TRPV1+ nociceptors, via interactions with dDCs, are essential in vivo regulators of interleukin-(IL)-23/IL-17 pathway cutaneous immune responses. This set of studies raised several intriguing questions including determining what the inputs and outputs of nociceptors are that regulate IL-23 production from dDCs and whether nociceptors play a role in distinct inflammatory contexts. In further experiments we determined that while TRPV1 itself is dispensable, nociceptor activity is essential to promote disease and local cytokine production. As we found that nociceptors are critical for cutaneous IL-23 production, we tested the effect of nociceptor ablation during a bacterial infection that depends on IL-23 for clearance. Surprisingly, the absence of NaV1.8+ nociceptors led to more severe skin pathology and bacterial dissemination suggesting that NaV1.8+ nociceptors are important for tissue protection and bacterial containment. In complementary studies assessing the role of nociceptors in atopic dermatitis (Type 2 inflammation), we found that TRPV1+ neurons did not regulate gross disease or the instructive cytokine thymic stromal lymphopoietin (TSLP), yet were required for full effector (IL-4) cytokine production. This suggests that nociceptors exert contextual specificity and are not exclusively pro-inflammatory in all cutaneous pathologies.
Based on the role for nociceptors in regulating cutaneous IL-23 and subsequent inflammation, we hypothesized that TRPV1+ nociceptors would be important in regulating IL-23-driven pathologies in the gut. However, we found no appreciable role for nociceptors in either an acute innate colitis or a spontaneous microbiota-driven colitis. While colitis is characterized by its gastrointestinal pathology, it affects the body systemically and we noted that in both models, mice lacking TRPV1+ nociceptors maintained healthier weights than their nerve-replete counterparts. This opens future avenues for exploration on how sensing of inflammation by nociceptors influences microbial communities, systemic metabolism, and sickness behavior.
In summary, we propose that sensory perception of inflammation by peripheral neurons exerts context-dependent effects on immunological processes. We speculate that there is the potential to uncover a modular design framework by which distinct lines of sensory neurons are triggered in specific settings and may contribute to regulating different aspects of inflammation through interactions with immune cell subsets.
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