Gut microbiota promotes pain chronicity in Myosin1A deficient male mice.

Chronic pain is a heavily debilitating condition and a huge socio-economic burden, with no efficient treatment. Over the past decade, the gut microbiota has emerged as an important regulator of nervous system's health and disease states. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented.

Formalin-evoked pain triggers sex-specific behavior and spinal immune response.

Mounting evidence shows sex-related differences in the experience of pain with women suffering more from chronic pain than men. Yet, our understanding of the biological basis underlying those differences remains incomplete. Using an adapted model of formalin-induced chemical/inflammatory pain, we report here that in contrast to male mice, females distinctly display two types of nocifensive responses to formalin, distinguishable by the duration of the interphase.

Differential regulation of cutaneous immunity by sensory neuron subsets.

The nervous and immune systems have classically been studied as separate entities, but there is now mounting evidence for bidirectional communication between them in various organs, including the skin. The skin is an epithelial tissue with important sensory and immune functions. The skin is highly innervated with specialized subclasses of primary sensory neurons (PSNs) that can be in contact with skin-resident innate and adaptive immune cells.

Cholinergic interneuron inhibition potentiates corticostriatal transmission in direct medium spiny neurons and rescues motor learning in parkinsonism.

Striatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson's disease. How this signal regulates the striatal network remains an open question.

Neuroimmune crosstalk in the skin: a delicate balance governing inflammatory processes.

With its unique structure and large numbers of immune cells, the skin is one of the body's first lines of defense against attacks from the environment. It is also innervated by a dense meshwork of primary sensory neurons, including nociceptive fibers specializing in the detection and transduction of harmful stimuli that can elicit pain. This tissue is, therefore, a key organ for studies of neuroimmune interactions and their impact on the host response to environmental challenges.

TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K current.

Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice.

Introducing the novel Cytoscape app TimeNexus to analyze time-series data using temporal MultiLayer Networks (tMLNs).

Integrating -omics data with biological networks such as protein-protein interaction networks is a popular and useful approach to interpret expression changes of genes in changing conditions, and to identify relevant cellular pathways, active subnetworks or network communities. Yet, most -omics data integration tools are restricted to static networks and therefore cannot easily be used for analyzing time-series data. Determining regulations or exploring the network structure over time requires time-dependent networks which incorporate time as one component in their structure.

Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions.

Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages.

Loss of bhlha9 Impairs Thermotaxis and Formalin-Evoked Pain in a Sexually Dimorphic Manner.

C-LTMRs are known to convey affective aspects of touch and to modulate injury-induced pain in humans and mice. However, a role for these neurons in temperature sensation has been suggested, but not fully demonstrated. Here, we report that deletion of C-low-threshold mechanoreceptor (C-LTMR)-expressed bhlha9 causes impaired thermotaxis behavior and exacerbated formalin-evoked pain in male, but not female, mice.

Cav3.2 T-type calcium channels shape electrical firing in mouse Lamina II neurons.

The T-type calcium channel, Cav3.2, is necessary for acute pain perception, as well as mechanical and cold allodynia in mice. Being found throughout sensory pathways, from excitatory primary afferent neurons up to pain matrix structures, it is a promising target for analgesics.

[Neuroimmune interactions in the skin: a link between pain and immunity].

Upon infection, our ability to eliminate pathogens depends mostly on our immune system. However, recent studies have shown that the nervous system plays a role in controlling infectious and inflammatory processes. Bidirectional functional interactions are established between the nervous and immune systems to protect tissue integrity.

Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain.

Primary sensory neurons are heterogeneous by myriad of molecular criteria. However, the functional significance of this remarkable heterogeneity is just emerging. We precedently described the GINIP neurons as a new subpopulation of non peptidergic C-fibers encompassing the free nerve ending cutaneous MRGPRD neurons and C-LTMRs.

Analysis of cutaneous MRGPRD free nerve endings and C-LTMRs transcriptomes by RNA-sequencing.

The skin is the largest sensory organ that is densely innervated by highly specialized sensory neurons allowing the detection of a wide range of stimulations including light touch, temperature, itch and pain. Our knowledge of the sets of genes instructing the functional specialization of sensory neurons is just emerging. In a previous study, we have identified a new Gαi inhibitory interacting protein (GINIP) that marks two distinct subsets of skin-innervating sensory neurons conveying noxious and pleasant touch: the MRGPRD-expressing C-fibers specialized in noxious touch and the TH(+)/TAFA4(+)/V-GLUT3(+) C-Low Threshold MechanoReceptors (C-LTMRs), part of neurons processing pleasant touch.

Transcriptional Profiling of Cutaneous MRGPRD Free Nerve Endings and C-LTMRs.

Cutaneous C-unmyelinated MRGPRD free nerve endings and C-LTMRs innervating hair follicles convey two opposite aspects of touch sensation: a sensation of pain and a sensation of pleasant touch. The molecular mechanisms underlying these diametrically opposite functions are unknown. Here, we used a mouse model that genetically marks C-LTMRs and MRGPRD neurons in combination with fluorescent cell surface labeling, flow cytometry, and RNA deep-sequencing technology (RNA-seq).

Acute heat-evoked temperature sensation is impaired but not abolished in mice lacking TRPV1 and TRPV3 channels.

The discovery of heat-sensitive Transient Receptor Potential Vanilloid ion channels (ThermoTRPVs) greatly advanced our molecular understanding of acute and injury-evoked heat temperature sensation. ThermoTRPV channels are activated by partially overlapping temperatures ranging from warm to supra-threshold noxious heat. TRPV1 is activated by noxious heat temperature whereas TRPV3 can be activated by warm as well as noxious heat temperatures.

TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice.

C-low-threshold mechanoreceptors (C-LTMRs) are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs.

Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor.

NKp46 is a cell surface receptor expressed on natural killer (NK) cells, on a minute subset of T cells, and on a population of innate lymphoid cells that produce IL-22 and express the transcription factor retinoid-related orphan receptor (ROR)-γt, referred to as NK cell receptor (NKR)(+)ROR-γt(+) cells. Here we describe Nkp46(iCre) knock-in mice in which the gene encoding the improved Cre (iCre) recombinase was inserted into the Nkp46 locus. This mouse was used to noninvasively trace cells expressing NKp46 in vivo.

Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt- lymphoid cells.

The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46(+) cells expresses retinoic acid receptor-related orphan receptor γt (RORγt) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46(+) cells lack RORγt and produce IFN-γ, like conventional Natural Killer (cNK) cells.

A novel mucosal RORγtNKp46 cell subset is a source of interleukin-22.

Lymphoid tissue-inducer cells are hematopoietic cells essential for the organogenesis of several lymphoid structures during both fetal and adult life, whereas natural killer cells are key effector lymphocytes of the innate immune system. A series of recent reports has identified RORγt(+)NKp46(+) interleukin-22-producing cells in gut and tonsils that share features with both lymphoid tissue-inducer cells and natural killer cells and that may be involved in mucosal immunity and homeostasis.

Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.

NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes.