Biology subjects

Ciccia, F.

Publications and source records attributed to Ciccia, F..

3 recordsLinked to original sources

bioRxiv2025

Distinct myeloid precursors and their interaction with mesenchymal cells orchestrate the spreading of psoriatic disease from the skin to the joints

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/665302v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@38c440org.highwire.dtl.DTLVardef@dc574dorg.highwire.dtl.DTLVardef@1e79f72org.highwire.dtl.DTLVardef@19508cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=109 HEIGHT=200 SRC="FIGDIR/small/603031v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c217b8org.highwire.dtl.DTLVardef@a340ceorg.highwire.dtl.DTLVardef@1f3c1d8org.highwire.dtl.DTLVardef@3b6fc9_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIGut microbiota-derived histamine activates enteric neurons via H3R C_LIO_LILocal intestinal H3R activation induces shift to homeostatic microglia in the spinal cord C_LIO_LICNS controlled decrease in endothelial leakiness resolves synovial inflammation C_LI

immunology↗

bioRxiv2022

Deficiencies of Runx3 and tissue-resident CD4+ intestinal epithelial lymphocytes link intestinal dysbiosis and inflammation in mouse and human spondyloarthropathy

ObjectiveDisturbances in immune regulation, intestinal microbial dysbiosis and intestinal inflammation characterize ankylosing spondylitis (AS), which is associated with RUNX3 loss-of-function variants. ZAP70W163C mutant (SKG) mice have reduced ZAP70 signaling, spondyloarthritis and ileitis. At intestinal epithelial interfaces, lamina propria Foxp3+ regulatory T cells (Treg) and intraepithelial CD4+CD8+TCR{beta}+ lymphocytes (CD4-IEL) control inflammation. TGF-{beta} and retinoic acid (RA)-producing dendritic cells are required for induction of Treg and for CD4-IEL differentiation from CD4+ conventional or Treg precursors, with upregulation of Runx3 and suppression of ThPOK. We investigated Treg, CD4-IEL, ZAP70 and Runx3 in SKG mice and AS patients. MethodsWe compared ileal Treg and CD4-IEL numbers and differentiation in BALB/c and SKG mice, and with ZAP70 inhibition, and related differentially-expressed genes in terminal ileum to ChIP-seq-identified Runx3-regulated genes. We compared proportions of CD4-IEL in ileum and CD4+8+ T cells in blood of AS patients and healthy controls. ResultsZAP70W163C or ZAP70 inhibition prevented intestinal CD4-IEL but not Foxp3+ Treg differentiation in context of TGF-{beta} and RA in vitro and in vivo, resulting in Runx3 and ThPOK dysregulation. CD4-IEL frequency and expression of tissue resident memory T-cell and Runx3-regulated genes was reduced in SKG intestine. Multiple under-expressed genes were shared with risk SNPs identified in human spondyloarthropathies. CD4-IEL were decreased in AS intestine. Double-positive T cells were reduced and Treg increased in AS peripheral blood. ConclusionHigh-affinity TCR-ZAP70 signalling is required for Runx3-mediated intestinal CD4-IEL differentiation from Treg. Genetically-encoded relative immunodeficiency of T cells underpins poor intestinal barrier control in mouse and human spondyloarthropathy. What is already known about this subject?Ankylosing spondylitis (AS) is associated with RUNX3 loss-of-function variants. Capacity of the AS T cell receptor repertoire to expand in response to infectious antigens is reduced. Foxp3+ regulatory T cells (Treg) are increased in AS intestine. ZAP70W163C mutant (SKG) mice have reduced ZAP70 signaling, spondyloarthritis (SpA) and ileitis. Intestinal epithelial Foxp3+ Treg and CD4+CD8+ cytotoxic lymphocytes (CD4-IEL) control local inflammation. CD4-IEL differentiate from Treg, with upregulation of Runx3 and suppression of ThPOK transcription factors. What does this study add?High-affinity TCR-ZAP70 signalling is required for Runx3-mediated intestinal CD4-IEL differentiation from Treg Intestinal CD4-IEL and circulating CD4+CD8+ T cells are reduced in AS while circulating Treg are increased. Impaired CD8 expression may be correctible by TNF inhibition in AS CD4+ T cells. Deficiencies of Runx3 and tissue-resident CD4-IEL link intestinal dysbiosis and inflammation in mouse and human SpA. How might this influence clinical practice or future developments?Genetically-encoded relative T immunodeficiency underpins poor intestinal barrier control in SpA

immunology↗