ABSTRACT
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.
Subject(s)
Immunity, Innate/immunology , Lymphocytes/immunology , Lymphocytes/pathology , Psoriasis/immunology , Psoriasis/pathology , Skin/immunology , Skin/pathology , Animals , Cell Differentiation , Cell Lineage , Chromatin/genetics , Disease Models, Animal , Female , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-23/immunology , Latent Class Analysis , Lymphocytes/classification , Male , Mice , Psoriasis/genetics , RNA, Small Cytoplasmic/genetics , Reproducibility of Results , Time FactorsABSTRACT
Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.
Subject(s)
Immunity, Innate/immunology , Lymphocytes/immunology , Lymphoid Progenitor Cells/immunology , Animals , Cell Differentiation/immunology , Cells, Cultured , Female , Humans , Interleukin-18 Receptor alpha Subunit/immunology , Lung/immunology , Mice , Mice, Inbred C57BL , Promyelocytic Leukemia Zinc Finger Protein/immunology , Signal Transduction/immunology , Single-Cell Analysis/methods , T Cell Transcription Factor 1/immunology , Transcription Factors/immunologyABSTRACT
An unexpected C-C bond cleavage has been revealed in the absence of metal. This observation has been exploited to develop an efficient approach toward 3,6-diarylpyridazines and 6-arylpyridazin-3-ones from simple and commercially available 1,3-dicarbonyl compounds and methyl ketones.
Subject(s)
Ketones/chemistry , Pyridazines/chemistry , Molecular StructureABSTRACT
An I(2) promoted domino protocol was developed to construct 2-acylbenzothiazoles from simple and readily available aromatic ketones/unsaturated methyl ketones and o-aminobenzenethiols. The reaction proceeded smoothly under metal-free and peroxide-free conditions.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/chemical synthesis , Carbon/chemistry , Hydrogen/chemistry , Iodine/chemistry , Catalysis , Chemistry Techniques, Synthetic , Cyclization , Oxidation-ReductionABSTRACT
A molecular I(2)-promoted sp(3) C-H bond dual-(het)arylation protocol was developed for the synthesis of 2,2-bisindolyl-1-arylethanones. Through a logical design, three mechanism-different reactions (iodination, Kornblum oxidation, and Friedel-Crafts reaction) were assembled in a single reactor. A variety of 2,2-bisindolyl-1-aryl ethanones were synthesized from simple and readily available aryl methyl ketones and indoles. In the reaction, metal, base, and ligand were all avoidable.
Subject(s)
Acetophenones/chemical synthesis , Iodine/chemistry , Acetophenones/chemistry , Molecular StructureABSTRACT
The sustainable byproduct catalyzed domino strategy has been performed for the facile synthesis of α-formyloxy and acetoxy ketones via iodination/nucleophilic substitution/hydrolyzation/oxidation sequences from simple and readily available aromatic ketones/unsaturated methyl ketones.
Subject(s)
Chemistry Techniques, Synthetic/methods , Green Chemistry Technology/methods , Halogenation , Ketones/chemistry , Ketones/chemical synthesis , Catalysis , Hydrolysis , Oxidation-ReductionABSTRACT
The title compound, C(12)H(10)N(2)O(2), was obtained unintentionally during the synthesis of 2-amino-5-(4-meth-oxy-phen-yl)furan-3-carbonitrile. In the crystal, weak inter-mol-ecular C-Hâ¯N and C-Hâ¯π inter-actions link the mol-ecules into columns propagating in [010].
