Skin-resident innate lymphoid cells converge on a pathogenic effector state
| Autor: | Roberto R. Ricardo-Gonzalez, Leif S. Ludwig, Georg Gasteiger, Holly R. Steach, Lina Kroehling, Maria Carolina Amezcua Vesely, Monika S. Kowalczyk, Autumn G. York, Mathias H. Skadow, Richard M. Locksley, Ruaidhri Jackson, Piotr Bielecki, Caroline B. M. Porter, Heather M. McGee, Aviv Regev, Hao Xu, Michal Slyper, Samantha J. Riesenfeld, Danielle Dionne, Will Bailis, Amanda J. Kedaigle, Elena Christian, Abigail Jarret, Richard A. Flavell, Elena Torlai Triglia, Paula Licona-Limón, Liming Tao, Mi Lian, Nicola Gagliani, Christoph Muus, Parastou Yaghoubi, Jan-Christian Hütter |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Time Factors Cellular differentiation Interleukin-23 Mice 0302 clinical medicine Small Cytoplasmic RNA Small Cytoplasmic 2.1 Biological and endogenous factors Innate Lymphocytes Aetiology skin and connective tissue diseases Skin Multidisciplinary Effector Innate lymphoid cell Cell Differentiation Chromatin Cell biology Latent Class Analysis Female medicine.symptom General Science & Technology 1.1 Normal biological development and functioning Inflammation Biology Autoimmune Disease Article 03 medical and health sciences Immune system Underpinning research Psoriasis Genetics medicine Animals Cell Lineage Transcription factor Innate immune system Animal Inflammatory and immune system Immunity Reproducibility of Results medicine.disease Immunity Innate body regions Disease Models Animal Emerging Infectious Diseases 030104 developmental biology Disease Models RNA 030217 neurology & neurosurgery |
| Zdroj: | Nature, vol 592, iss 7852 Nature |
| Popis: | Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum—even at steady state—reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling. In studies using mouse models of psoriasis, a spectrum of innate lymphoid cell types is reconfigured and converges via multiple trajectories on a type 3-like state, demonstrating the range and flexibility of innate lymphoid cell responses in the skin. |
| Databáze: | OpenAIRE |
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