RESUMO
Professional antigen-presenting cells (APCs) in the skin include dendritic cells, monocytes, and macrophages. They are highly dynamic, with the capacity to enter skin from the peripheral circulation, patrol within tissue, and migrate through lymphatics to draining lymph nodes. Skin APCs are endowed with antigen-sensing, -processing, and -presenting machinery and play key roles in initiating, modulating, and resolving cutaneous inflammation. Skin APCs are a highly heterogeneous population with functionally specialized subsets that are developmentally imprinted and modulated by local tissue microenvironmental and inflammatory cues. This review explores recent advances that have allowed for a more accurate taxonomy of APC subsets found in both mouse and human skin. It also examines the functional specificity of individual APC subsets and their collaboration with other immune cell types that together promote adaptive T cell and regional cutaneous immune responses during homeostasis, inflammation, and disease.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/imunologia , Células de Langerhans/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Pele/imunologia , Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Movimento Celular , Homeostase , Humanos , Inflamação , Ativação Linfocitária , CamundongosRESUMO
Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.
Assuntos
Nociceptores , Dor , Animais , Camundongos , Dor/imunologia , Dor/metabolismo , Nociceptores/metabolismo , Transcriptoma , Camundongos Endogâmicos C57BL , Inflamação/imunologia , Masculino , Macrófagos/imunologia , Macrófagos/metabolismo , Modelos Animais de Doenças , Trombospondina 1/metabolismo , Trombospondina 1/genética , Pele/imunologia , Pele/metabolismo , Pele/patologia , Zimosan , Análise de Célula Única , Neuroimunomodulação , Perfilação da Expressão Gênica , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.
Assuntos
Psoríase/imunologia , Animais , Comorbidade , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Camundongos , Psoríase/diagnóstico , Psoríase/genética , Pele/imunologia , Pele/patologia , Fenômenos Fisiológicos da Pele/imunologiaRESUMO
The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.
Assuntos
Retrovirus Endógenos/fisiologia , Homeostase , Inflamação/microbiologia , Inflamação/patologia , Microbiota , Animais , Bactérias/metabolismo , Cromossomos Bacterianos/genética , Dieta Hiperlipídica , Inflamação/imunologia , Inflamação/virologia , Interferon Tipo I/metabolismo , Queratinócitos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/metabolismo , Retroelementos/genética , Transdução de Sinais , Pele/imunologia , Pele/microbiologia , Linfócitos T/imunologia , Transcrição GênicaRESUMO
Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.
Assuntos
Imunidade Inata/imunologia , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Células Receptoras Sensoriais/imunologia , Pele/imunologia , Canais de Cátion TRPV/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Candida albicans/imunologia , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos , Pele/microbiologia , Staphylococcus aureus/imunologia , Canais de Cátion TRPV/genéticaRESUMO
Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.
Assuntos
Imunidade Adaptativa , Quimiotaxia , Relógios Circadianos , Células Dendríticas/imunologia , Linfonodos/imunologia , Vasos Linfáticos/imunologia , Pele/imunologia , Idoso , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Linfonodos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pele/metabolismo , Fatores de TempoRESUMO
Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
Assuntos
Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Mycobacterium leprae/imunologia , Pele/imunologia , Adolescente , Adulto , Idoso , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/patologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Queratinócitos/patologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/microbiologia , Hanseníase Virchowiana/patologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/microbiologia , Hanseníase Tuberculoide/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , RNA-Seq , Análise de Célula Única , Pele/microbiologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , TranscriptomaRESUMO
The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.
Assuntos
Comunicação Celular , Diferenciação Celular , Interleucina-13/metabolismo , Células de Langerhans/metabolismo , Pele/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Alérgenos/farmacologia , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Células Cultivadas , Bases de Dados Genéticas , Humanos , Interleucina-13/genética , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Pele/citologia , Pele/efeitos dos fármacos , Pele/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , TranscriptomaRESUMO
Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
Assuntos
Autoimunidade , Encéfalo/imunologia , Linhagem da Célula , Encefalomielite Autoimune Experimental/imunologia , Intestinos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Autoimunidade/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sinalização do Cálcio , Líquido Cefalorraquidiano/imunologia , Líquido Cefalorraquidiano/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Cloridrato de Fingolimode/farmacologia , Perfilação da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T , Células HEK293 , Humanos , Imunossupressores/farmacologia , Intestinos/efeitos dos fármacos , Microscopia Intravital , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fenótipo , Estudos Prospectivos , RNA-Seq , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Análise de Célula Única , Pele/efeitos dos fármacos , Pele/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/transplante , TranscriptomaRESUMO
Due to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.
Assuntos
Imunoterapia , Interleucina-2 , Lúpus Eritematoso Sistêmico , Pele , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/imunologia , Interleucina-2/imunologia , Pele/imunologia , Imunoterapia/métodos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ativação Linfocitária/imunologia , Feminino , Adulto , MasculinoRESUMO
Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.
Assuntos
Células Epiteliais , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Psoríase , Pele , Animais , Humanos , Doença Crônica , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Pele/imunologia , Pele/patologia , Pele/metabolismoRESUMO
It's crucial for skin to establish efficient defense strategies. Liu et al. reveal that the transcription factor ZNF750 recruits the histone demethylase KDM1A to silence pattern recognition receptors in the outer epidermis, making their expression limited to deeper, undifferentiated keratinocytes to address threats penetrating the skin.
Assuntos
Queratinócitos , Pele , Fatores de Transcrição , Humanos , Queratinócitos/metabolismo , Queratinócitos/imunologia , Pele/imunologia , Pele/metabolismo , Animais , Fatores de Transcrição/metabolismo , Histona Desmetilases/metabolismo , Epiderme/metabolismo , Epiderme/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Proteínas de Ligação a DNA/metabolismoRESUMO
The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (TLR3, IFIH1/MDA5, and DDX58/RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of TLR3. Our findings explain how the skin's surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs.
Assuntos
Histona Desmetilases , Inflamação , Queratinócitos , Receptores de Reconhecimento de Padrão , Pele , Fatores de Transcrição , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Humanos , Queratinócitos/metabolismo , Animais , Camundongos , Receptores de Reconhecimento de Padrão/metabolismo , Receptores de Reconhecimento de Padrão/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Pele/imunologia , Pele/patologia , Pele/metabolismo , Inflamação/imunologia , Diferenciação Celular/imunologia , Psoríase/imunologia , Psoríase/genética , Psoríase/metabolismo , Camundongos Knockout , Inativação Gênica , Camundongos Endogâmicos C57BL , Proteínas Supressoras de TumorRESUMO
Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.
Assuntos
Antígeno B7-1 , Folículo Piloso , Inflamação , Pele , Células-Tronco , Linfócitos T Reguladores , Cicatrização , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Cicatrização/imunologia , Pele/imunologia , Pele/lesões , Pele/patologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Inflamação/imunologia , Folículo Piloso/imunologia , Antígeno B7-1/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reepitelização/imunologia , Movimento Celular/imunologia , Proliferação de CélulasRESUMO
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
Assuntos
Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Interleucina-17 , Animais , Humanos , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pele/imunologia , Pele/patologia , Pele/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética , Psoríase/imunologia , Psoríase/metabolismo , Epitélio/imunologia , Epitélio/metabolismo , Camundongos Knockout , Transdução de Sinais/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Modelos Animais de Doenças , Ácido Láctico/metabolismo , Doença Crônica , Inflamação/imunologia , Camundongos Endogâmicos C57BLRESUMO
Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
Assuntos
Imunidade Adaptativa , Bactérias/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Microbiota/imunologia , Pele/imunologia , Linfócitos T/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos TransgênicosRESUMO
Skin wounds heal by coordinated induction of inflammation and tissue repair, but the initiating events are poorly defined. Here we uncover a fundamental role of commensal skin microbiota in this process and show that it is mediated by the recruitment and the activation of type I interferon (IFN)-producing plasmacytoid DC (pDC). Commensal bacteria colonizing skin wounds trigger activation of neutrophils to express the chemokine CXCL10, which recruits pDC and acts as an antimicrobial protein to kill exposed microbiota, leading to the formation of CXCL10-bacterial DNA complexes. These complexes and not complexes with host-derived DNA activate pDC to produce type I IFNs, which accelerate wound closure by triggering skin inflammation and early T cell-independent wound repair responses, mediated by macrophages and fibroblasts that produce major growth factors required for healing. These findings identify a key function of commensal microbiota in driving a central innate wound healing response of the skin.
Assuntos
Células Dendríticas/imunologia , Fibroblastos/imunologia , Macrófagos/imunologia , Microbiota/imunologia , Neutrófilos/imunologia , Pele/imunologia , Animais , Células Cultivadas , Quimiocina CXCL10/metabolismo , Humanos , Imunidade Inata , Inflamação , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/patologia , Simbiose , CicatrizaçãoRESUMO
The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these 'tissue' signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies.
Assuntos
Intestinos/imunologia , Pele/imunologia , Linfócitos T Reguladores/imunologia , Adaptação Fisiológica , Animais , Meio Ambiente , Humanos , Camundongos , Timo/imunologiaRESUMO
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.