Pain Relief Dependent on IL-17–CD4 ⁺ T Cell–β-Endorphin Axis in Rat Model of Brachial Plexus Root Avulsion After Electroacupuncture Therapy

Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. While the proinflammatory properties of IL-17 are key to its host-protective capacity, unrestrained IL-17 signaling is associated with immunopathology, autoimmune disease, and cancer progression. In this review we discuss both the activators and the inhibitors of IL-17 signal transduction, and also the physiological implications of these events. We highlight the surprisingly diverse means by which these regulators control expression of IL-17-dependent inflammatory genes, as well as the major target cells that respond to IL-17 signaling.

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

Systemically administered opioids are among the most powerful analgesics for treating severe pain. Several negative side effects (respiratory depression, addiction, nausea and confusion) and the risk of opioid‐induced hyperalgesia accompany opioid administration. One other side effect is the potential of opioids to suppress the immune response and thereby to increase the vulnerability to infections. The link between opioids and immunosuppression has been investigated both in vitro and in vivo as well as in patients. However, the results are inconsistent: Exogenous opioids such as morphine and fentanyl have been found to impair the function of macrophages, natural killer cells and T‐cells and to weaken the gut barrier in vitro and in animal studies. In epidemiological studies, high doses and the initiation of opioid therapy for non‐malignant pain have been correlated with a higher risk of infectious diseases such as pneumonia. However clear randomized controlled studies are missing. Furthermore, immune cells including neutrophils, macrophages and T‐cells have been shown to secrete endogenous opioid peptides, which then bind to peripheral opioid receptors to relieve inflammatory and neuropathic pain. In addition to cytokines, hormones and bacterial products, the release of opioid peptides is stimulated by the application of exogenous opioids. In summary, there is a reciprocal interaction between the immune system and endogenous as well as exogenous opioids. Further to the existing epidemiological studies, controlled clinical studies are needed in the future to elucidate the role of the opioid–immune system interaction in patients and to determine its clinical relevance. Linked Articles This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc