Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis.

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.

Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity.

Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.

Inflammatory thoughts can upset your guts.

Peripheral neurons and immune cells interact to modulate inflammation, but whether the brain can control this process is unknown. In a recent issue of Cell, Koren et al. (2021) show that peripheral inflammation is encoded in the insular cortex and that later re-activation of these neurons triggers inflammation.

Age-Related Dopaminergic Innervation Augments T Helper 2-Type Allergic Inflammation in the Postnatal Lung.

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.

Lung dopaminergic nerves facilitate the establishment of TH2 resident memory cells in early life.

BACKGROUND: Allergic asthma develops from allergen exposure in early childhood and progresses into adulthood. The central mediator of progressive allergic asthma is allergen-specific, TH2-resident memory cells (TRMs). Although the crosstalk between nerves and immune cells plays an established role in acute allergic inflammation, whether nerves facilitate the establishment of TH2-TRMs in the immature lung following early life allergen exposure is unknown. OBJECTIVES: The aim of this study was to identify nerve-derived signals that act in TH2 effector cells to regulate the tissue residency in the immature lung. METHODS: Following neonatal allergen exposure, allergen-specific TH2-TRMs were tracked temporally and spatially in relationship to developing sympathetic nerves in the lung. Functional mediators of dopamine signaling in the establishment of TH2-TRMs were identified by in vitro bulk RNA-sequencing of dopamine-treated TH2 cells followed by in vivo assessment of candidate genes using adoptive transfer of TH2 cells with viral gene knockdown. RESULTS: This study found that sympathetic nerves produce dopamine and reside in proximity to TH2 effector cells during the contraction phase following neonatal allergen exposure. Dopamine signals via DRD4 on TH2 cells to elevate IL2RA and epigenetically facilitate type 2 cytokine expression. Blockade of dopamine-DRD4 signaling following neonatal allergen exposure impairs lung residence of TH2 cells and ameliorates anamnestic inflammation in adults. CONCLUSIONS: These results demonstrate that maturing sympathetic nerves enable a dopamine-enriched lung environment in early life that promotes the establishment of allergen-specific TH2-TRMs. The dopamine-DRD4 axis may provide a therapeutic target to modify allergic asthma progression from childhood to adulthood.

Neuronal Regulation of Cutaneous Immunity.

The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system-pathogen recognition, secretion of soluble mediators-are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.

Risk associated with perioperative red blood cell transfusion in cranial surgery.

We assessed the impact of intra- and postoperative RBC transfusion on postoperative morbidity and mortality in cranial surgery. A total of 8924 adult patients who underwent cranial surgery were identified in the 2006-2011 American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Patients undergoing a biopsy, radiosurgery, or outpatient surgery were excluded. Propensity scores were calculated according to demographic variables, comorbidities, and preoperative laboratory values. Patients who had received RBC transfusion were matched to those who did not, by propensity score, preoperative hematocrit level, and by length of surgery, as an indirect measure of potential intraoperative blood loss. Logistic regression was used to predict adverse postoperative outcomes. A total of 625 (7%) patients were transfused with one or more units of packed RBCs. Upon matching, preoperative hematocrit, length of surgery, and emergency status were no longer different between transfused and non-transfused patients. RBC transfusion was associated with prolonged length of hospitalization (OR 1.6, 95% CI 1.2-2.2), postoperative complications (OR 2.8, 95% CI 2.0-3.8), 30-day return to operation room (OR 2.0, 95% CI 1.3-3.2), and 30-day mortality (OR 4.3, 95% CI 2.4-7.6). RBC transfusion is associated with substantive postoperative morbidity and mortality in patients undergoing both elective and emergency cranial surgery. These results suggest judicious use of transfusion in cranial surgery, consideration of alternative means of blood conservation, or pre-operative restorative strategies in patients undergoing elective surgery, when possible.

CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.

Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is acutely induced by diverse cytokine stimuli in many tissues, was expressed constitutively in AMs in response to steady-state GM-CSF signaling. Cish deficiency led to the generation of foamy AMs and the accumulation of pulmonary surfactant. These phenotypic changes were associated with enhanced activation of STAT5, AKT, and ERK and increased expression of the gene encoding the transcription factor GATA2. RNA-seq analysis of Cish−/− AMs revealed a set of dysregulated immune and lipid-process modules, including the increased expression of genes enriched for GATA2-binding motifs. Last, Cish-deficient, bone marrow­derived macrophages showed increased Gata2 expression and accumulated more lipid upon incubation with bronchoalveolar lavage fluid compared with Cish-sufficient cells. Thus, CISH is part of a feedback loop that constrains homeostatic cytokine signaling and Gata2 expression to maintain AM identity and function.

Inflammatory Responses with Left Ventricular Compromise after Induction of Myocardial Infarcts in Sheep (Ovis aries).

Ischemic myocardial disease is a major cause of death among humans worldwide; it results in scarring and pallor of the myocardium and triggers an inflammatory response that contributes to impaired left ventricular function. This response includes and is evidenced by the production of several inflammatory cytokines including TNFα, IL1ß, IL4, IFNγ, IL10 and IL6. In the current study, myocardial infarcts were induced in 6 mo old male castrated sheep by ligation of the left circumflex obtuse marginal arteries (OM 1 and 2). MRI was used to measure parameters of left ventricular function that include EDV, ESV, EF, SVI, dp/dt max and dp/dt min at baseline and at 4 wk and 3 mo after infarct induction. We also measured serum concentrations of an array of cytokines. Postmortem histologic findings corroborate the existence of left ventricular myocardial injury and deterioration. Our data show a correlation between serum cytokine concentrations and the development of myocardial damage and left ventricular functional compromise.

Influence of estrogen depletion and salt loading on renal angiotensinogen expression in the mRen(2).Lewis strain.

The mRen(2).Lewis (mRen2) strain is an ANG II-dependent model of hypertension expressing marked sex differences in blood pressure and tissue injury that also exhibits estrogen and salt sensitivity. Because estrogen and salt influence angiotensinogen (AGT), circulating and renal expression of the protein were assessed in the mRen2 using a sensitive and specific ELISA. Hemizygous female and male mRen2 were placed on normal (1% NaCl, NS)- or high (8% NaCl, HS)-salt diets from 5 to 15 wk of age while a separate NS cohort was ovariectomized (OVX). The OVX mRen2 exhibited higher blood pressure (184 +/- 6 vs. 149 +/- 5 mmHg, n = 6), a 16-fold increase in urinary AGT (uAGT) (0.2 +/- 0.02 vs. 0.01 +/- 0.01 microg x kg(-1) x day(-1), P < 0.01), but no change in proteinuria (PROT). Excretion of AGT was correlated with blood pressure and PROT in the female groups. The HS diet led to higher blood pressure (224 +/- 8 mmHg), a 180-fold increase in uAGT (1.8 +/- 0.2 microg x kg(-1) x day(-1)), and increased PROT (98 +/- 9 vs. 7 +/- 1 mg x kg(-1) x day(-1)). Compared with females, NS males expressed higher excretion of uAGT (3.0 +/- 0.4 microg x kg(-1) x day(-1)) and PROT (32 +/- 5 mg x kg(-1) x day(-1)); both were increased eightfold with HS (uAGT: 23 +/- 3 microg x kg(-1) x day(-1); PROT: 285 +/- 28 mg x kg(-1) x day(-1)) without a change in blood pressure. Although uAGT was markedly higher in the OVX and HS groups, neither renal cortical AGT mRNA or protein expression was increased. Moreover, AGT release in cortical slices was similar for the NS and HS females. We conclude that the increase in uAGT with estrogen depletion or HS likely may be a biomarker for glomerular damage reflecting filtration of the circulating protein in the mRen2.

Intimate neuro-immune interactions: breaking barriers between systems to make meaningful progress.

The nervous system is often viewed as an isolated system that integrates information from the environment and host. Recently, there has been a renewed focus exploring the concept that the nervous system also communicates across biological systems. Specifically, several high profile studies have recently highlighted the importance of neuro-immune communication in the context of homeostasis, central nervous system disorders, host defense and injury. Here, we discuss the history of shared mechanisms and interconnectedness of the nervous, immune and epithelial compartments. In light of these overlapping mechanisms, it is perhaps unsurprising that neuro-immune-epithelial signaling plays a key role in regulating diverse biological phenomena. In this review, we explore recent breakthroughs in understanding neuro-immune signaling to highlight the importance of interdisciplinary approaches to biomedical research and the future development of novel therapeutics.

Preserving Airway Smooth Muscle Contraction in Precision-Cut Lung Slices.

Precision-cut lung slices (PCLS) are ideal for measuring small airway contraction. However, these measurements are currently limited to acute exposure scenarios that typically last a few minutes to a few hours. Using an insulin-supplemented culture medium, we prolong the small airway contractility in mouse PCLS for up to two weeks. Compared to conventional culture medium, insulin-supplemented culture medium provides no additional benefit in preserving cellular viability or airway structure. However, it protects the airway smooth muscle (ASM) against a loss of smooth muscle myosin heavy chain (SMMHC) expression. We elucidate the significance of this new culture medium for chronic disease modeling of IL-13-induced airway hyper-responsiveness.

Early versus late Gamma Knife radiosurgery following transsphenoidal surgery for nonfunctioning pituitary macroadenomas: a multicenter matched-cohort study.

OBJECTIVE Gamma Knife radiosurgery (GKRS) is frequently used to treat residual or recurrent nonfunctioning pituitary macroadenomas. There is no consensus as to whether GKRS should be used early after surgery or if radiosurgery should be withheld until there is evidence of imaging-defined progression of tumor. Given the high incidence of adenoma progression after subtotal resection over time, the present study intended to evaluate the effect of timing of radiosurgery on outcome. METHODS This is a multicenter retrospective review of patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery followed by GKRS from 1987 to 2015 at 9 institutions affiliated with the International Gamma Knife Research Foundation. Patients were matched by adenoma and radiosurgical parameters and stratified based on the interval between last resection and radiosurgery. Operative results, imaging data, and clinical outcomes were compared across groups following early (≤ 6 months after resection) or late (> 6 months after resection) radiosurgery. RESULTS After matching, 222 patients met the authors' study criteria (from an initial collection of 496 patients) and were grouped based on early (n = 111) or late (n = 111) GKRS following transsphenoidal surgery. There was a greater risk of tumor progression after GKRS (p = 0.013) and residual tumor (p = 0.038) in the late radiosurgical group over a median imaging follow-up period of 68.5 months. No significant difference in the occurrence of post-GKRS endocrinopathy was observed (p = 0.68). Thirty percent of patients without endocrinopathy in the early cohort developed new endocrinopathies during the follow-up period versus 27% in the late cohort (p = 0.84). Fourteen percent of the patients in the early group and 25% of the patients in the late group experienced the resolution of endocrine dysfunction after original presentation (p = 0.32). CONCLUSIONS In this study, early GKRS was associated with a lower risk of radiological progression of subtotally resected nonfunctioning pituitary macroadenomas compared with expectant management followed by late radiosurgery. Delaying radiosurgery may increase patient risk for long-term adenoma progression. The timing of radiosurgery does not appear to significantly affect the rate of delayed endocrinopathy.

[Is the severity of occupational asthma related to the molecular weight of the allergen?]. / La sévérité de l'asthme professionnel est-elle liée au poids moléculaire de l'allergène?

INTRODUCTION: The aim of the study was to compare the characteristics of occupational asthma (OA) resulting from sensitisation to allergens of high (HMW) or low (LMW) molecular weight. METHODS: All new cases of allergic OA seen in an occupational health department between January 2001 and March 2004 were included. The patients underwent a standardised assessment including a questionnaire, skin tests, spirometry and measurement of non-specific bronchial reactivity. They were divided into 2 groups depending on the molecular weight of the causal agent (groups HMW and LMW). RESULTS: 77 patients were included, 30 in the HMW group and 47 in the LMW group. No significant difference in severity at the time of diagnosis was found between the two groups (symptoms, spirometry, PD20 methacholine) but the time between the first symptoms and diagnosis was longer in the HMW group (7.1 +/- 7.8 years against 3.2 +/- 4.1 years, p = 0.01). Atopy was more common in the HMW group (57% vs. 27%, p = 0.01). CONCLUSION: The severity of OA at the time of diagnosis does not appear to be influenced by the molecular weight of the causal agent.

Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats.

The mRen2.Lewis congenic strain is an estrogen-sensitive model of hypertension whereby estrogen depletion produces a significant and sustained increase in blood pressure. The recent identification of G protein-coupled receptor 30 (GPR30) as a third estrogen receptor isotype prompted us to test the hypothesis that this novel receptor exhibits beneficial cardiovascular actions in the hypertensive female mRen2.Lewis rat. Intact female, ovariectomized female (OVX), and male mRen2.Lewis rats were treated with the selective GPR30 agonist G-1 or vehicle via osmotic minipump for 2 wk. G-1 significantly reduced systolic blood pressure in OVX (178 +/- 7 to 142 +/- 10 mm Hg, P < 0.001, n = 8) but not intact female (144 +/- 3 to 143 +/- 5 mm Hg, P > 0.05, n = 5) or male mRen2.Lewis rats (207 +/- 7 to 192 +/- 5 mm Hg, P > 0.05, n = 7). G-1 did not alter uterine or body weight in OVX, suggesting activation of a receptor distinct from estrogen receptor-alpha and -beta. In isolated aortic rings from OVX, G-1 reduced constriction in response to angiotensin II. Vascular angiotensin-converting enzyme and angiotensin type 1 receptor mRNA were also lower, whereas angiotensin-converting enzyme-2 mRNA was increased. G-1 treatment in OVX was not associated with alterations in either endothelial nitric oxide synthase expression or acetylcholine-induced relaxation. Immunohistochemical staining for GPR30 was evident in both the intima and media of the aorta. We conclude that the novel estrogen receptor GPR30 may contribute to the beneficial cardiovascular actions of estrogen in female mRen2.Lewis rats through regulation of vascular components of the renin-angiotensin system.

Gastro-oesophageal reflux prevalence and relationship with bronchial reactivity in asthma.

The relationship between asthma and gastro-oesophageal reflux (GER) is controversial. In an allergy department, GER prevalence was evaluated in asthmatics, with a view to judging the potential influence of GER on asthma. One hundred and five asthmatics were recruited and co-investigated for GER and lung function. Descriptive analysis was performed, patients with (GER+) and without (GER-) GER were then compared, and finally, stepwise regression analysis was used. GER prevalence was 32%. Lung parameters did not differ between GER+ and GER- patients. When restricting analysis to GER+ patients, bronchial reactivity was closely correlated to the number of reflux episodes (NRE) (r=0.983; p=0.001). When comparing patients with more than 15 reflux episodes x day(-1) (n=50), with those having less (n=43), no differences were found in lung function and GER parameters. However, there was a positive correlation between the provocative dose of methacholine causing forced expiration volume to fall 20% from the baseline and NRE in patients with NRE>15 (r=0.561; p=0.05). In conclusion, gastro-oesophageal reflux was observed in a third of the asthma patients studied. These data do not support a firm aetiological relationship between gastro-oesophageal reflux and asthma, but do suggest an association between the number of reflux episodes and bronchial hyperresponsiveness.