Regulation of the immune response of the skin by the sensory nervous system

La peau constitue l’une des premières lignes de défense contre les menaces extérieures. Elle présente un système nerveux sensoriel particulièrement développé capable d’interagir fonctionnellement avec son système immunitaire. Cependant ces interactions neuro-immunes sont encore très mal comprises et des analyses plus fines sont nécessaires pour décrypter le réel potentiel de ces neurones à réguler les réponses immunitaires. Nos travaux, présentés ici, se concentrent sur le rôle d'une sous-population de neurones sensoriels innervant la peau identifiée par le marqueur GINIP. La déplétion conditionnelle de ces neurones in vivo (souris GINIP-DTR), à révélé leur rôle central dans le contrôle de l'inflammation et de la réparation des tissus cutanés suite à une exposition aux UV. Les souris dépourvues de neurones GINIP+ présentent une augmentation du nombre de macrophages inflammatoires et des lésions profondes du derme comparées aux souris sauvages. Afin de disséquer les mécanismes moléculaires impliqués, nous nous sommes intéressés à la protéine XXX, un médiateur produit par une sous population de neurones GINIP+, les C-LTMR. In vitro, XXX réduit l’expression de cytokines pro-inflammatoires et favorise la production de médiateurs anti-inflammatoires par les macrophages. In vivo, l’absence de cette molécule (souris XXX-KO) accélère la différentiation des monocytes infiltrant en macrophages résidents, les rendant incapables de résoudre la fibrose du derme induite par les UV. Ces résultats suggèrent que les C-LTMR régulent fonctionnellement des cellules myéloïdes via XXX.The skin is one of the body’s first lines of defense against external threats. This complex tissue contains a highly developed sensory nervous system and an immune system can cooperate to maintain homeostasis. However, these neuro-immune interactions are still poorly understood and further analyses are necessary to understand their role in skin immune response and tissue repair.The goal of the work presented here is to explore the role of a subset of skin sensory neurons identified by the marker GINIP. In vivo, the conditional depletion of these neurons (GINIP-DTR mice) revealed their central role in the control of inflammation and in the repair of skin exposed to UV (ultrat-violet) irradiation. Compared to wild type controls, mice lacking GINIP+ neurons displayed an increase in inflammatory macrophage number in the dermis associated with deep damage. To decipher the molecular mechanisms involved, we focused on the protein XXX, a mediator produced by a subset of GINIP+ neurons, the C-LTMR. In vitro, XXX reduced the expression of pro-inflammatory cytokines and promoted anti-inflammatory factors by macrophages. In vivo, the lack of this molecule (XXX KO mice) accelerated the differentiation of infiltrating monocytes in dermis resident macrophages, making them unable to resolve the fibrosis induced by UV treatment. These results suggest that C-LTMR regulates the myeloid cell response to UV irradiation via XXX

Natural killer cell engagers in cancer immunotherapy: Next generation of immuno‐oncology treatments

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Interactions neuro-immunes dans la peau : Un lien entre douleur et immunité

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. The skin is one of the first lines of defense against external threats and has a particularly well-developed neuroimmune system. Challenges to the skin activate neurons specialized in pain perception, which regulate immune cell functions and recruitment to tissues. We illustrate the importance of such neuroimmune regulation here, through the example of several skin diseases

CD150-dependent hematopoietic stem cell sensing of Brucella instructs myeloid commitment

International audienceSo far, hematopoietic stem cells (HSC) are considered the source of mature immune cells, the latter being the only ones capable of mounting an immune response. Recent evidence shows HSC can also directly sense cytokines released upon infection/inflammation and pathogen-associated molecular pattern interaction while keeping a long-term memory of previously encountered signals. Direct sensing of danger signals by HSC induces early myeloid commitment, increases myeloid effector cell numbers, and contributes to an efficient immune response. Here, by using specific genetic tools on both the host and pathogen sides, we show that HSC can directly sense B. abortus pathogenic bacteria within the bone marrow via the interaction of the cell surface protein CD150 with the bacterial outer membrane protein Omp25, inducing efficient functional commitment of HSC to the myeloid lineage. This is the first demonstration of direct recognition of a live pathogen by HSC via CD150, which attests to a very early contribution of HSC to immune response

Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions

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Nociceptive sensory neurons promote CD8 T cell responses to HSV-1 infection

International audienceAbstract Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav 1.8 + sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav 1.8 -expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav 1.8 + sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

International audienceIt has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients