IL-17+ Mast Cell/T Helper Cell Axis in the Early Stages of Acne.

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.

Effect of thermal spring water on human dendritic cell inflammatory response.

BACKGROUND: Hydrotherapy appears as a valuable therapeutic tool in the management of patients suffering from chronic skin inflammatory diseases. Nevertheless, the underlying immune mechanisms of these beneficial effects remain poorly understood. To better understand the biological effects of thermal spring water on the immune system, we investigated the effects of Avène thermal spring water (ASW) on dendritic cells as key cells participating in the control of the immune response. METHODS: Dendritic cells (DCs) were generated from human monocytes and matured with LPS in ASW-based culture medium or in dexamethasone supplemented culture medium as an anti-inflammatory treatment. The phenotypes and abilities of these DCs to produce cytokines and induce allogeneic T cell response was next assessed. RESULTS: We showed that ASW modulated the differentiation of monocytes into DCs and impacted the DC maturation upon LPS priming. We observed a reduction of the CD83, CD86, CD1a and HLA-DR molecule expression and a decrease of IL-12 and IL-23 production whereas IL-10 production was increased. LPS-primed DCs generated in presence of ASW exhibited a reduced capacity to induce naive CD4+ T cell proliferation and IFN-γ and IL-17 production. CONCLUSION: Our study showed that ASW is endowed with an immunomodulatory potential. ASW limits the DC stimulatory capacity of Th1 and Th17 cell responses by impairing their maturation, IL-12 and IL-23 production and accessory cell function.

U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish.

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is the most abundant FUS interactor. Here, we report that components of the U1 snRNP core particle (Sm proteins and U1 snRNA), but not the mature U1 snRNP-specific proteins (U1-70K, U1A and U1C), co-mislocalize with FUS to the cytoplasm in ALS patient fibroblasts harboring mutations in the FUS nuclear localization signal (NLS). Similar results were obtained in HeLa cells expressing the ALS-causing FUS R495X NLS mutation, and mislocalization of Sm proteins is RRM-dependent. Moreover, as observed with FUS, knockdown of any of the U1 snRNP-specific proteins results in a dramatic loss of SMN-containing Gems. Significantly, knockdown of U1 snRNP in zebrafish results in motor axon truncations, a phenotype also observed with FUS, SMN and TDP-43 knockdowns. Our observations linking U1 snRNP to ALS patient cells with FUS mutations, SMN-containing Gems, and motor neurons indicate that U1 snRNP is a component of a molecular pathway associated with motor neuron disease. Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target.