IL-17-producing-ST2+ILC2 plays a pathogenic role in lung inflammation

Publication date: Available online 3 April 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Ting Cai, Jinxin Qiu, Yan Ji, Wenjing Li, Zhaoyun Ding, Caixia Suo, Jiali Chang, Jingjing Wang, Rui He, Youcun Qian, Xiaohuan Guo, Liang Zhou, Huiming Sheng, Lei Shen, Ju Qiu
BackgroundIL-17 plays a pathogenic role in asthma. ST2⁻iILC2s (inflammatory group 2 innate lymphoid cells) driven by IL-25 can produce IL-17, while ST2⁺nILC2s (natural ILC2s) produce few IL-17.ObjectiveWe characterized the ST2⁺IL-17⁺ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2⁺IL-17⁺ILC2s.MethodsLung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1^−/−, Rorc^gfp/gfp and Ahr^−/− mice was examined by flow cytometry. Bone marrow transfer experiment was performed to evaluate hematopoietic MyD88 signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naïve ILC2s treated with IL-33, leukotrienes and inhibitors for NFAT, p38, JNK or NF-κB. The pathogenesis of IL-17⁺ILC2s was determined by transferring wild-type or Il17^−/−ILC2s to Rag2^−/−Il2rg^−/− mice which were further induced lung inflammation. Finally, the expression of 106 ILC2 signature genes was compared between ST2⁺IL-17⁺ILC2s and ST2⁺IL-17⁻ILC2s.ResultsPapain or IL-33 treatment boosted IL-17 production from ST2⁺ILC2s (we name them as ILC217), but not ST2⁻ILC2s. Ahr, but not RORγt, facilitated the production of IL-17 by ILC217s. Hematopoietic compartment of MyD88 signaling is essential for the induction of ILC217s. IL-33 works in synergy with leukotrienes, which signal through NFAT activation, to promote IL-17 in ILC217s. Il17^−/− ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed few GM-CSF.ConclusionDuring lung inflammation, IL-33 and leukotrienes synergistically induce ILC217s. ILC217s are highly pathogenic and unexpected source for IL-17 in lung inflammation.

Teaser

During lung inflammation, IL-33 and leukotrienes synergistically boost endogenous production of IL-17 from tissue-resident ST2⁺ILC2s. IL-17-producing ST2⁺ILC2s are highly pathogenic by recruiting leukocytes to airways and may be involved in severe forms of asthma.


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Global Supply and Demand of Opioids for Pain Management

Abstract

Purpose of Review

The goal of this review is to evaluate the global supply and demand of opioids used for pain management and discuss how it relates to the utilization of opioids around the world. The purpose of the review is also to determine the factors that contribute to inappropriate pain management.

Recent Findings

The total global production of opium for opioid manufacturing is enough to supply the growing global demands. However, licit opioids are only consumed by 20% of the world population. Most people throughout the world had no access to opioid analgesics for pain relief in case of need. Opioid misuse and abuse is not only a phenomena plague by the USA but globally across many countries.

Summary

Many countries have a lack of availability of opioids, contributing factors being strict government regulations limiting access, lack of knowledge of the efficacy of opioid analgesics in treating acute and chronic pain and palliative care, and the stigma that opioids are highly addictive. For the countries in which opioids are readily available and prescribed heavily, diversion, misuse, abuse, and the resurgence of heroin have become problems leading to morbidity and mortality. It is pertinent to find a balance between having opioids accessible to patients in need, with ensuring that opioids are regulated along with other illicit drugs to decrease abuse potential.

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The Evidence for the Role of Nutraceuticals in the Management of Pediatric Migraine: a Review

Abstract

Purpose of Review

Nutraceuticals are a form of complementary and alternative medicine that is commonly used by children and adolescents with migraine. In this review, observational studies, randomized controlled trials, systematic reviews, and meta-analyses on the efficacy and safety of single compound nutraceuticals for the management of migraine in children and adolescents were identified through a literature search of MEDLINE, Embase, and EBM Reviews—Cochrane Central Register of Controlled Trials.

Recent Findings

Twenty-one studies were reviewed, of which 11 were observational studies, 7 were randomized controlled trials, and 3 were systematic reviews. Six different nutraceuticals were included in the review: vitamin D, riboflavin, coenzyme Q10, magnesium, butterbur, and polyunsaturated fatty acids. All but three of the studies assessed the role of nutraceuticals in migraine prevention, while three studies evaluated the role of intravenous magnesium for acute migraine management. Overall, the quality and size of the studies were limited.

Summary

Due to low quality evidence and limited studies, no definite conclusions can be drawn on the efficacy of nutraceuticals for the treatment of pediatric migraine. Future studies are warranted in order to establish evidence upon which to define the role of nutraceuticals in this patient population.

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America’s Opioid Epidemic: a Comprehensive Review and Look into the Rising Crisis

Abstract

Purpose of Review

In the USA, there has been a sharp increase in heroin, prescription opiate, and illicitly manufactured fentanyl abuse with overdoses tripling since the 1990s. Several states have been deemed as "high-burden" abuse states where there is a greater proportion of synthetic opiate use. During the same period that prescription limitations were initially implemented throughout the country, the fentanyl epidemic started nationwide.

Recent Findings

In the setting of data demonstrating an almost fourfold increase in overdose deaths from 1999 to 2008, states began restricting access to Food and Drug Agency (FDA) approved opioid medications. Another factor further exacerbating the opioid crises is that the cost of all formulations of naloxone has increased significantly over the past several years.

Summary

In order to combat the opioid epidemic, stricter prescribing practices and prescription-monitoring programs have been instituted. Also, improvements in abuse-deterrent strategies for all opioid preparations can play an important role by increasing the safety of these medications and is a major focus of the FDA.

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Is Migraine Primarily a Metaboloendocrine Disorder?

Abstract

Purpose of the Review

The goals of this review are to evaluate recent studies regarding comorbidity between migraine and different metabolic and endocrine disorders and to discuss the role of insulin resistance as a common pathogenetic mechanism of these diseases.

Recent Findings

Recently, several studies showed that migraine is associated with insulin resistance, a condition in which a normal amount of insulin induces a suboptimal physiological response. All the clinical studies that used the oral glucose tolerance test to examine insulin sensitivity found that, after glucose load, there is in migraine patients a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls. On the contrary, no association was found between migraine and type 2 diabetes, while type 1 diabetes seems to have a protective effect in the disease. Obesity and hypertension were shown to be risk factors for both episodic and chronic migraine. Metabolic syndrome has been recently associated mainly with migraine with aura and is now considered a risk factor also for medication overuse headache. Finally, a bidirectional association between migraine and hypothyroidism has been recently demonstrated, suggesting that common genetic or autoimmune mechanisms underlie both diseases.

Summary

Recent studies showed that insulin receptor signaling and the related physiological responses are altered in migraine and may have a relevant pathogenic role in the disease. Further studies are warranted in order to better elucidate mechanisms underlying insulin resistance in migraine in order to develop new therapeutic strategies for this debilitating disease.

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Evidence-Based Non-Pharmacological Therapies for Fibromyalgia

Abstract

Purpose of Review

Fibromyalgia (FM) is the second most common rheumatologic pain disorder after osteoarthritis with a multisystem presentation. While the treatment of FM in a clinical setting incorporates both pharmacologic and non-pharmacologic modalities, the present investigation reviews evolving literature on cognitive behavioral and complementary medical therapies. The recent medical literature on FM was reviewed between 2012 and 2017 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis on randomized controlled trials, meta-analyses, and evidence-based treatment guidelines.

Recent Findings

Cognitive behavioral therapy continues to play a significant role in the non-medical therapy of FM. It is especially helpful in high catastrophizing patients as evidenced by recent studies that note changes in the brain on functional magnetic resonance imaging. Mindfulness meditation can be helpful in improving pain symptoms and pain perception. No particular diet is found to have a meaningful impact in FM; however, various diets including low fermentable oligo- di –monosaccharides and polyols diet, gluten free, and hypocaloric may be helpful in ameliorating gastrointestinal distress in select patient populations. Current literature does not support the routine use of acupuncture for improving pain or quality of life in FM; however, given its benign side effect profile, it should not be discouraged.

Summary

Goals for symptom management and pain control should be set early, and patient engagement remains critical in the management of this complex pain presentation. While low quality evidence exists for most non-pharmacologic treatment modalities for FM, CBT and mindfulness meditation show promise for future investigation.

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New Advances in Acute Postoperative Pain Management

Abstract

Purpose of Review

Postoperative pain remains one of the most common challenges following inpatient and outpatient surgeries. With our advances in modern medicine, pain following surgical procedures still remains a challenge, though significant accomplishments have been made over the past few decades. This article highlights some of the promising new advances and approaches in postoperative pain management.

Recent Findings

Over the last decade, Enhanced Recovery after Surgery (ERAS) pathways and protocols are becoming the benchmark standards for enhancing postoperative recovery. Multimodal analgesia (MMA) is an essential component of such care. Further, in the wake of serious and persistent concern on the opioid epidemic in the USA, there has been a recent renewal of interest in non-opioid alternatives or adjuncts in controlling postoperative pain, often in the context of MMA. Intravenous (IV) acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), magnesium, ketamine, dexmedetomidine, liposomal bupivacaine, and newer neuraxial and peripheral regional techniques as well as patient-controlled modalities are gaining importance. Gabapentinoids have become popular but recent meta-analytic reviews have cast doubt on their routine use in perioperative settings. Among opioids, sublingual sufentanil, IV oxycodone, and iontophoretic transdermal fentanyl hold promise. Acupuncture and transcutaneous electrical nerve stimulation may be useful as adjuncts in MMA packages. Genetic testing, derivatives of herbal preparations, and an extended role of acute pain services may emerge as potential areas of importance in the future. There are, however, critical gaps in good quality evidence in many of the practice guideline recommendations.

Summary

In the era of opioid epidemic, several lines of evidence have emerged to support non-opioid-based drugs and approaches along with a few newer opioid formulations for postoperative pain management, although more research is needed to find the right balance of efficacy and safety.

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