Nat Commun 2021 Apr 12;12(1):2185. doi: 10.1038/s41467-021-22479-4.

Therapeutic B-cell depletion reverses progression of Alzheimer’s disease

Ki Kim ^# 1, Xin Wang ^# 1, Emeline Ragonnaud ^# 1, Monica Bodogai ^# 1, Tomer Illouz ^2 3 4, Marisa DeLuca ¹, Ross A McDevitt ⁵, Fedor Gusev ⁶, Eitan Okun ^2 3 4, Evgeny Rogaev ^6 7 8 9, Arya Biragyn ¹⁰

• PMID: 33846335
• PMCID: PMC8042032
• DOI: 10.1038/s41467-021-22479-4

Abstract

The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ⁺ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.

Nat Commun. 2020 Dec 11;11(1):6363. doi: 10.1038/s41467-020-19931-2.

Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system

Grégoire Chevalier ¹, Eleni Siopi ², Laure Guenin-Macé ³, Maud Pascal ^1 2, Thomas Laval ³, Aline Rifflet ⁴, Ivo Gomperts Boneca ⁴, Caroline Demangel ³, Benoit Colsch ⁵, Alain Pruvost ⁵, Emeline Chu-Van ⁵, Aurélie Messager ⁵, François Leulier ⁶, Gabriel Lepousez ², Gérard Eberl ⁷, Pierre-Marie Lledo ⁸

• PMID: 33311466
• PMCID: PMC7732982
• DOI: 10.1038/s41467-020-19931-2

Abstract

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

 Br J Dermatol. 2018 Sep;179(3):669-678. doi: 10.1111/bjd.16498.Epub 2018 Jun 21.

Itch in dermatomyositis: the role of increased skin interleukin-31

H J Kim ^1 2 3, M Zeidi ^1 2, D Bonciani ^1 2 4, S M Pena ², J Tiao ^1 2, S Sahu ^1 2, V P Werth ^1 2

• PMID: 29494763
• PMCID: PMC6119520
• DOI: 10.1111/bjd.16498

Abstract

Background: Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch.

Objectives: To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch.

Methods: Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM.

Results: Among 191 patients with DM, 50·8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0·34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0·67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31-producing cells, and CD4⁺ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells.

Conclusions: Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM.

J Invest Dermatol. 2021 Apr 1;S0022-202X(21)01129-5. doi: 10.1016/j.jid.2021.03.015.Online ahead of print.

Mechanisms of broad-band ultraviolet B irradiation-induced itch in mice

Liang Cao ¹, Xueping Yue ¹, Yonghui Zhao ¹, Lixia Du ¹, Zili Xie ¹, Yi Yuan ¹, Sha Zhang ², Feng Li ², Jing Feng ³, Hongzhen Hu ¹

• PMID: 33812858
• DOI: 10.1016/j.jid.2021.03.015

Abstract

Although sunburn can produce severe uncontrollable itching, the underlying mechanisms of ultraviolet (UV) irradiation-induced itch are poorly understood because of a lack of experimental animal models of sunburn itch. Here we established a sunburn-related mouse model and found that Broad-band UVB (BB-UVB) irradiation elicited scratching but not wiping behavior in mice. By using a combination of live-cell Ca²⁺ imaging and quantitative RT-PCR on dorsal root ganglion (DRG) neurons, hematoxylin and eosin staining, immunofluorescence staining of skin preparations, behavioral testing, in combination with genetic and pharmacological approaches, we showed that TRPV1-positive DRG neurons but not mast cells are involved in BB-UVB irradiation-induced itch. Moreover, both genetic and pharmacological inhibition of TRPV1 function significantly alleviated BB-UVB irradiation-induced itch response. Collectively, our results suggest that BB-UVB irradiation evokes itch sensation in mice through promoting TRPV1 channel function in DRG neurons and provide potential therapeutic targets for sunburn-related itch.

Keywords: BB-UVB; Itch model; Sunburn-related itch; TRPV1.

Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca21 signals in mice

Miho Shiratori-Hayashi, PhD,a Chiharu Yamaguchi, MPharm,a Kazushi Eguchi, MPharm,a Yuto Shiraishi, BPharm,a Keita Kohno, BPharm,a Katsuhiko Mikoshiba, MD, PhD,b,c,d Kazuhide Inoue, PhD,e Motohiro Nishida, PhD,f,g and Makoto Tsuda, PhDa 

Background: Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Objective: We aimed to determine the mechanisms of persistent activation of astrocytic STAT3 in chronic itch conditions. Methods: To determine the factors that are required for persistent activation of astrocytic STAT3, Western blotting and calcium imaging with cultured astrocytes or spinal cord slices were performed. Thereafter, chronic itch model mice were used for genetic and behavioral experiments to confirm the role of the factors determined to mediate persistent STAT3 activation from in vitro and ex vivo experiments in chronic itch.

Results: IP3 receptor type 1 (IP3R1) knockdown in astrocytes suppressed IL-6–induced persistent STAT3 activation and expression of lipocalin-2 (LCN2), an astrocytic STAT3- dependent inflammatory factor that is required for chronic itch. IP3R1-dependent astrocytic Ca21 responses involved Ca21 influx through the cation channel transient receptor potential canonical (TRPC), which was required for persistent STAT3 activation evoked by IL-6. IL-6 expression was upregulated in dorsal root ganglion neurons in a mouse model of chronic itch. Dorsal root ganglion neuron–specific IL-6 knockdown, spinal astrocyte–specific IP3R1 knockdown, and pharmacologic spinal TRPC inhibition attenuated LCN2 expression and chronic itch.

Conclusion: Our findings suggest that IP3R1/TRPC channel– mediated Ca21 signals elicited by IL-6 in astrocytes are necessary for persistent STAT3 activation, LCN2 expression, and chronic itch, and they may also provide new targets for therapeutic intervention. (J Allergy Clin Immunol 2021;147:1341-53.)

Key words: Contact dermatitis, chronic itch, astrocytes, STAT3, lip- ocalin-2, Ca21 signal, IP3R1, TRPC, IL-6, primary afferent sensory neuron

Epithelia-sensory neuron crosstalk underlies cholestatic itch induced by lysophosphatidylcholine

Yong Chen, Zi-Long Wang, Michele Yeo, Qiao-Juan Zhang, Ana E. López- Romero, Hui-Ping Ding, Xin Zhang, Qian Zeng, Sara L. Morales-Lázaro, Carlene Moore, Ying-Ai Jin, Huang-He Yang, Johannes Morstein, Andrey Bortsov, Marcin Krawczyk, Frank Lammert, Manal Abdelmalek, Anna Mae Diehl, Piotr Milkiewicz, Andreas E. Kremer, Jennifer Y. Zhang, Andrea Nackley, Tony E. Reeves, Mei- Chuan Ko, Ru-Rong Ji, Tamara Rosenbaum, Wolfgang Liedtke

BACKGROUND & AIMS

Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of anti-pruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.

METHODS

Pruritogenicity of LPC, LPA’s precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC’s pruritogenicity involving keratinocyte-TRPV4 was studied using genetic and pharmacological approaches, cultured keratinocytes, ion channel physiology and structural-computational modeling. Activation of pruriceptor-sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in-vitro and ex-vivo Ca²⁺-imaging assays. Sera from primary biliary cholangitis (PBC) patients were used for measuring the levels of LPC and miR-146a.

RESULTS

LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. 3D-structural modeling, site-directed mutagenesis and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4-activation by LPC induced extracellular release of miR-146a, which activated TRPV1⁺-sensory neurons to cause itch. Both LPC and miR-146a levels were elevated in sera of PBC patients with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates.

CONCLUSIONS

We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron crosstalk, whereby it directly activates skin keratinocyte-TRPV4, which rapidly release miR-146a to activate skin-innervating TRPV1⁺-pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons and central neural pathways supporting pruriception.

The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch

ABSTRACT

Acute and chronic itch are burdensome manifestations of skinpathologies including allergic skin diseases and atopic dermatitis,but the underlying molecular mechanisms are not well understood.Cysteinyl leukotrienes (CysLTs), comprising LTC4,LTD4, and LTE4,areproduced by immune cells during type 2 inflammation. Here, weuncover a role for LTC4and its signaling through the CysLT receptor2 (CysLT2R) in itch.Cysltr2transcript is highly expressed in dorsalroot ganglia (DRG) neurons linked to itch in mice. We also detectedCYSLTR2in a broad population of human DRG neurons. Injection ofleukotriene C4(LTC4) or its nonhydrolyzable form NMLTC4,butnei-ther LTD4nor LTE4, induced dose-dependent itch but not pain be-haviors in mice. LTC4-mediated itch differed in bout duration andkinetics from pruritogens histamine, compound 48/80, and chloro-quine. NMLTC4-induced itch was abrogated in mice deficient forCysltr2or when deficiency was restricted to radioresistant cells. Itchwas unaffected in mice deficient forCysltr1,Trpv1, or mast cells(WShmice). CysLT2R played a role in itch in the MC903 mouse modelof chronic itch and dermatitis, but not in models of dry skin or com-pound 48/80- orAlternaria-induced itch. In MC903-treated mice,CysLT levels increased in skin over time, andCysltr2−/−mice showeddecreased itch in the chronic phase of inflammation. Collectively,our study reveals that LTC4acts through CysLT2R as its physiologicalreceptor to induce itch, and CysLT2R contributes to itch in a model ofdermatitis. Therefore, targeting CysLT signaling may be a promisingapproach to treat inflammatory itch.

Keywords: itch, neuroimmune, atopic dermatitis, skin, inflammation

Transl Psychiatry. 2019 Aug 5;9(1):189. doi: 10.1038/s41398-019-0525-3.

Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice

Jing Sun ¹, Jingxuan Xu ², Yi Ling ¹, Fangyan Wang ³, Tianyu Gong ⁴, Changwei Yang ⁴, Shiqing Ye ⁴, Keyue Ye ⁴, Dianhui Wei ⁴, Ziqing Song ⁴, Danna Chen ⁴, Jiaming Liu ^5 6

• PMID: 31383855
• PMCID: PMC6683152
• DOI: 10.1038/s41398-019-0525-3

Abstract

Alzheimer’s disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and ¹H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.

The influence of adolescent nicotine exposure on ethanol intake and brain gene expression

PLoS One . 2018 Jun 18;13(6):e0198935. doi: 10.1371/journal.pone.0198935. eCollection 2018.

Constanza P Silva ¹, William J Horton ², Michael J Caruso ¹, Aswathy Sebastian ³, Laura C Klein ¹, Istvan Albert ³, Helen M Kamens ¹

• PMID: 29912970
• PMCID: PMC6005571
• DOI: 10.1371/journal.pone.0198935

Abstract

Nicotine and alcohol are often co-abused. Adolescence is a vulnerable period for the initiation of both nicotine and alcohol use, which can lead to subsequent neurodevelopmental and behavioral alterations. It is possible that during this vulnerable period, use of one drug leads to neurobiological alterations that affect subsequent consumption of the other drug. The aim of the present study was to determine the effect of nicotine exposure during adolescence on ethanol intake, and the effect of these substances on brain gene expression. Forty-three adolescent female C57BL/6J mice were assigned to four groups. In the first phase of the experiment, adolescent mice (PND 36-41 days) were exposed to three bottles filled with water or nicotine (200 μg/ml) for 22 h a day and a single bottle of water 2 h a day for six days. In the second phase (PND 42-45 days), the 4-day Drinking-in-the-Dark paradigm consisting of access to 20% v/v ethanol or water for 2h or 4h (the last day) was overlaid during the time when the mice did not have nicotine available. Ethanol consumption (g/kg) and blood ethanol concentrations (BEC, mg %) were measured on the final day and whole brains including the cerebellum, were dissected for RNA sequencing. Differentially expressed genes (DEG) were detected with CuffDiff and gene networks were built using WGCNA. Prior nicotine exposure increased ethanol consumption and resulting BEC. Significant DEG and biological pathways found in the group exposed to both nicotine and ethanol included genes important in stress-related neuropeptide signaling, hypothalamic-pituitary-adrenal (HPA) axis activity, glutamate release, GABA signaling, and dopamine release. These results replicate our earlier findings that nicotine exposure during adolescence increases ethanol consumption and extends this work by examining gene expression differences which could mediate these behavioral effects.

Transient receptor potential ankyrin 1 (TRPA1) positively regulates imiquimod‐induced, psoriasiform dermal inflammation in mice

YanZhou1,2 | DanHan1,2 BoWang4 | ZhenruiShi2 Samuel T. Hwang2 TaylorFollansbee3 | XuesongWu2 | SebastianYu2 | | DanT.Domocos3 | MirelaCarstens3 | EarlCarstens3 |

1Department of Dermatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

2Department of Dermatology, University of California, Davis, California

3Department of Neurobiology, Physiology and Behavior, University of California, Davis, California

4Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

Abstract

Transient receptor potential ankyrin 1 (TRPA1), a membrane protein ion channel, is known to mediate itch and pain in skin. The function of TRPA1, however, in psori‐ asiform dermatitis (PsD) is uncertain. Herein, we found that expression of TRPA1 is highly up‐regulated in human psoriatic lesional skin. To study the role of TRPA1 in PsD, we assessed Psoriasis Severity Index (PSI) scores, transepidermal water loss (TEWL), skin thickness and pathology, and examined dermal inflammatory infiltrates, Th17‐related genes and itch‐related genes in c57BL/6 as wild‐type (WT) and TRPA1 gene knockout (KO) mice following daily application of topical IMQ cream for 5 days. Compared with WT mice, clinical scores, skin thickness change and TEWL scores were similar on day 3, but were significantly decreased on day 5 in IMQ‐treated TRPA1 KO mice (vs WT mice), suggesting reduced inflammation and skin barrier de‐ fects. Additionally, the relative area of epidermal Munro’s microabscesses and mRNA levels of neutrophil inducible chemokines (S100A8, S100A9 and CXCL1) were de‐ creased in the treated skin of TRPA1 KO mice, suggesting that neutrophil recruitment was impaired in the KO mice. Furthermore, mast cells, CD31+ blood vascular cells, CD45+ leukocytes and CD3+ T cells were all reduced in the treated skin of TRPA1 KO mice. Lastly, mRNA expression levels of IL‐1β, IL‐6, IL‐23, IL‐17A, IL‐17F and IL‐22 were decreased in TRPA1 KO mice. In summary, these results suggest a key role for TRPA1 in psoriasiform inflammation and raising its potential as a target for therapeu‐ tic intervention.

KEYWORDS

imiquimod, inflammation, itch, mice, psoriasis, TRPA1