Journal Club-2021.05.28

Runx1 Determines Nociceptive Sensory Neuron Phenotype and Is Required for Thermal and Neuropathic Pain

Chih-Li ChenDaniel C BroomYang LiuJoriene C de NooijZhe LiChuan CenOmar Abdel SamadThomas M JessellClifford J WoolfQiufu Ma

Abstract

In mammals, the perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by nociceptive sensory neurons. The molecular mechanisms responsible for the specification of distinct sensory modality are, however, largely unknown. We show here that Runx1, a Runt domain transcription factor, is expressed in most nociceptors during embryonic development but in adult mice, becomes restricted to nociceptors marked by expression of the neurotrophin receptor Ret. In these neurons, Runx1 regulates the expression of many ion channels and receptors, including TRP class thermal receptors, Na+-gated, ATP-gated, and H+-gated channels, the opioid receptor MOR, and Mrgpr class G protein coupled receptors. Runx1 also controls the lamina-specific innervation pattern of nociceptive afferents in the spinal cord. Moreover, mice lacking Runx1 exhibit specific defects in thermal and neuropathic pain. Thus, Runx1 coordinates the phenotype of a large cohort of nociceptors, a finding with implications for pain therapy.

Journal club 2021-05-21

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

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.

Journal club 2021-05-13

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

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.

Journal club 2021.05.07

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

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.

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