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Interleukin-36y-producing macrophages drive IL-17-mediated fibrosis.

ABSTRACT: Biomaterials induce an immune response and mobilization of macrophages, yet identification and phenotypic characterization of functional macrophage subsets in vivo remain limited. We performed single-cell RNA sequencing analysis on macrophages sorted from either a biologic matrix [urinary bladder matrix (UBM)] or synthetic biomaterial [polycaprolactone (PCL)]. Implantation of UBM promotes tissue repair through generation of a tissue environment characterized by a T helper 2 (Th2)/interleukin (IL)–4 immune profile, whereas PCL induces a standard foreign body response characterized by Th17/IL-17 and fibrosis. Unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle after UBM implantation. In the PCL tissue environment, we identified a CD9 hi+ IL-36y + macrophage subset that expressed Th17-associated molecules. These macrophages were virtually absent in mice lacking the IL-17 receptor, suggesting that they might be involved in IL-17–dependent immune and autoimmune responses. Identification and comparison of the unique phenotypical and functional macrophage subsets in mouse and human tissue samples suggest broad relevance of the new classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide targets for potential therapeutic modulation in tissue repair and pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE138027 | GEO | 2019/10/10

REPOSITORIES: GEO

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Mouse Th17 T cells, IL-23 stimulated

Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.

2020-03-25 | PXD016633 | Pride

CIP2A negatively regulates Th17 differentiation

Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.

2020-05-26 | PXD010612 | Pride

Distinct lactation-associated macrophages exist in murine mammary tissue and human milk

Project description:Macrophages are involved in immune defense, organogenesis and tissue homeostasis. They also contribute to the different phases of mammary gland remodeling during development, pregnancy and involution post-lactation. Yet, less is known about the dynamics of mammary gland macrophages in the lactation stage. Here, we describe a macrophage population present during lactation in mice. By multi-parameter flow cytometry and single-cell RNA sequencing we reveal this population as distinct from the two resident macrophage subsets present pregestationally. These lactation-induced macrophages (LiMacs) are predominantly monocyte-derived and expand by proliferation in situ concomitant with nursing. LiMacs develop independently of IL-34 but require CSF-1 signaling and are partly microbiota-dependent. Locally, they reside adjacent to the basal cells of the alveoli and extravasate into the milk. Moreover, we also found several macrophage subsets in human milk, resembling LiMacs. Collectively, these findings reveal the emergence of unique macrophages in the mammary gland and milk during lactation.

2023-06-23 | PXD041711 | Pride

RORγt inhibition selectively targets IL-17 producing human iNKT and γδ-T cells enriched in Spondyloarthritis while preserving IL-22 responses

Project description:Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but how they contribute to disorders such as SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells showed profound IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed a unique Th17 skewed phenotype and gene expression profile. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, these findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.

2018-11-17 | GSE122624 | GEO

The TNF family member TL1A induces IL-22 secretion in committed human TH17 cells via IL-9 induction

Project description:TL1A contributes to the pathogenesis of several chronic inflammatory diseases, including Inflammatory Bowel Diseases by enhancing TH1, TH17, and TH2 responses. TL1A mediates a strong co-stimulation of these TH subsets particularly of mucosal CCR9+ T cells. However, the signaling pathways that TL1A induces in different TH subsets are incompletely understood. Here, we investigated the function of TL1A on human TH17 cells. TL1A together with TGF- IL-6, and IL-23 enhanced the secretion of IL-17 and IFN- from human CD4+ memory T cells. TL1A induced the expression of the transcription factors BATF and T-bet that correlated with the secretion of IL-17 and IFN-. In contrast, TL1A alone induced high levels of IL-22 in memory CD4+ T cells and committed TH17 cells. However, TL1A did not enhance expression of IL-17A in TH17 cells. Expression of the transcription factor aryl hydrocarbon receptor that regulates expression of IL-22 was not affected by TL1A. We performed transcriptome analysis of TH17 cells to determine genes that are transcriptionally regulated by TL1A. transcriptome analysis revealed increased expression of IL-9 in response to TL1A.

2016-10-25 | GSE89133 | GEO

Role of PIP5K1a in human Th17 gene expression

Project description:This data was performed as part of Revu et al, "Human IL-17A protein expression is controlled through a PIP5K1a-dependent ARS2 checkpoint". IL-17 secreted by TH17 cells is beneficial for microbial control, but causes inflammation and pathological tissue remodeling in autoimmunity. Hence TH17 differentiation and IL-17 production must be tightly regulated, but to date this has been defined only in terms of transcriptional control. Phosphatidyinositols are second messengers activated during T cell activation that transduce signals from the TCR and costimulatory receptors at the cell membrane. Here we show phosphatidylinositol(4,5)bisphosphate (PIP2) was unexpectedly enriched in the nucleus of human TH17 cells, dependent on the kinase PIP5K1, and that blockade of PIP5K1 impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in Th1 or Th2 cells and these subsets did not require PIP5K1 for cytokine production. In multiple sclerosis patient T cells, IL-17 production elicited by myelin basic protein could be inhibited by PIP5K1 blockade. Surprisingly, PIP5K1 blockade did not alter IL17A mRNA levels or stability in TH17 cells. Instead, analysis of PIP5K1-interacting proteins revealed that PIP5K1 targets ARS2, a nuclear cap binding complex scaffold protein, to facilitate ARS2 binding to IL17A mRNA and subsequent IL-17 protein expression, uncovering a new mechanism for regulating IL-17A protein production and suggesting a novel mechanism of translation control of cytokines.

2023-05-15 | GSE232436 | GEO

Proteomic analysis reveals a protective role of specific macrophage subsets in liver repair

Project description:Macrophages are a heterogeneous population of immune cells that play central roles in a broad range of biological processes, including the resolution of inflammation. Although diverse macrophage subpopulations have been identified, the characterization and functional specialization of certain macrophage subsets in inflamed tissues remain unclear. Here we uncovered a key role of specific macrophage subsets in tissue repair using proteomics, bioinformatics and functional analyses. We isolated two hepatic monocyte-derived macrophage subpopulations: Ly6ChiCX3CR1lo macrophages and Ly6CloCX3CR1hi macrophages during distinct phases of acute liver injury and employed label-free proteomics approach to profile the proteome of these cells. We found that the wound healing- and endocytosis-related proteins were specifically enriched in Ly6CloCX3CR1hi macrophages. Intriguingly, 12/15-lipoxygenase (Alox15), the most strongly up-regulated protein in Ly6CloCX3CR1hi macrophages, was identified as a specific marker for these macrophages. In co-culture systems, Ly6CloCX3CR1hi macrophages specifically induced hepatocyte proliferation. Furthermore, selective depletion of this population in CD11b-diphtheria toxin receptor mice significantly delayed liver repair. Overall, our studies shed light on the functional specialization of distinct macrophage subsets in the resolution of inflammation.

2019-10-08 | PXD011958 | Pride

Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines

Project description:To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites Trypanosoma cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen Leishmania mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. Trypanosoma cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. Keywords: Bone marrow macrophage response to intracellular parasites and cytokines We analyzed a series MEEBO arrays on which were hybed RNA amplified from bone marrow-derived macrophages from C57BL/6 mice. Macrophages infected with L. mexicana or T. cruzi or stimulated by LPS, IFNG, IL-4, IL-10, TNF, IFNB, or IL-17 were compared to one another as well as to uninfected, unstimulated control macrophages. All experiments were performed over a 24 h timecourse with timepoints taken at 2 h, 6 h, 12 h, and 24 h.

2010-04-13 | E-GEOD-20087 | biostudies-arrayexpress

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2016-10-24 | E-GEOD-71155 | biostudies-arrayexpress

Tissue macrophage subsets derived from regenerating muscle

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