Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/719492

Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

Aschenbrenner, D.·Quaranta, M.·Banerjee, S.·Ilott, N.·Jansen, J.·Steere, B. A.·Chen, Y.-H.·Ho, S.·Cox, K.·Oxford IBD Cohort Investigators,·Arancibia-Carcamo, C. V.·Coles, M.·Gaffney, E.·Travis, S.·Denson, L. A.·Kugathasan, S.·Schmitz, J.·Powrie, F.·Sansom, S.·Uhlig, H. H.
View original source ↗Export metadata ↓

Abstract

BACKGROUND & AIMSDysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine. METHODSWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTSWe characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1/IL-1{beta} and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSIONOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohns disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1/IL-1{beta}-targeting therapies upstream of IL-23. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/719492v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@16598faorg.highwire.dtl.DTLVardef@11e5116org.highwire.dtl.DTLVardef@15d831borg.highwire.dtl.DTLVardef@4a697e_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Aschenbrenner, D., Quaranta, M., Banerjee, S., Ilott, N., Jansen, J., Steere, B. A., Chen, Y.-H., Ho, S., Cox, K., Oxford IBD Cohort Investigators,, Arancibia-Carcamo, C. V., Coles, M., Gaffney, E., Travis, S., Denson, L. A., Kugathasan, S., Schmitz, J., Powrie, F., Sansom, S., Uhlig, H. H.. 2019-07-31. Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23. https://doi.org/10.1101/719492

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

γδ T cell-derived IL-17A aggravates experimental epidermolysis bullosa acquisita in response to IL-1β

Epidermolysis bullosa acquisita (EBA) is a mucocutaneous autoimmune blistering disorder mediated by autoantibodies against type VII collagen and subsequent splitting of the dermal-epidermal junction. Interleukin (IL)-17A promotes the production of chemokines and cytokines involved in neutrophil recruitment and activation, suggesting that IL-17A may contribute to EBA pathogenesis. We aimed to clarify the role of IL-17A in experimental EBA. Using an antibody transfer-induced EBA mouse model, we demonstrate that IL-17A promotes disease development, as pharmacological blockade of IL-17A with a neutralizing antibody ameliorated skin lesions. Gamma-delta ({gamma}{delta}) T cells were identified as the predominant cellular source of IL-17A, supported by the attenuated disease phenotype observed in {gamma}{delta}TCR-deficient mice. In addition, CD4+ T cells and neutrophils contributed to IL-17A production in experimental EBA. Mechanistically, IL-1-beta, rather than IL-23, was identified as a critical mediator of IL-17A production by {gamma}{delta} T cells in vitro, consistent with our in vivo findings. Whereas EBA severity was not reduced in IL-23p19-deficient mice, disease was markedly attenuated in IL-1R-deficient animals. Together, our study provides the first evidence that {gamma}{delta} T cell-derived IL-17A plays a pivotal role in experimental EBA and identifies a previously unrecognized IL-1{beta}/{gamma}{delta} T cell/IL-17A axis that expands current understanding of EBA immunopathogenesis.

immunology↗
bioRxiv2026

A mammalian fibroblast zoo reveals barriers to cross-species virus replication and differential regulation of antiviral immunity

Virus zoonosis represents a continual threat to humans. Viruses emerge in humans directly or indirectly through interactions with mammals. However, our understanding of virus-host susceptibility across the diversity of mammals is limited and experimental model systems are restricted to a very small set of model organisms. Mammals are highly diverse and different habitats, lifestyles, diets, and exposures to different pathogens have driven substantial genetic diversity. We generated a library of primary fibroblasts across 86 mammalian species and used these cells to build an atlas of virus-host susceptibility across a panel of arboviruses that infect diverse mammals including humans. Perturbing the innate immune system revealed some virus-host pairs where restriction is controlled by the immune system and others where there is an incompatibility with host factors. Transcriptomic profiling of the library in response to virus sensing mimicked by poly(I:C) or antiviral signaling with type I interferon reveals a core set of conserved genes that respond as well as substantial species- and order-specific responses. Together these data provide a comparative atlas of innate immune responses across mammals and offer a window into how these systems have evolved across animals.

immunology↗
bioRxiv2026

A reporter mouse model to map RIG-I expression and function in vivo

The cytosolic RNA sensor RIG-I is a critical component of the innate immune response to RNA viruses, yet few tools exist to track RIG-I in vivo. Herein, we report the development of a RIG-I reporter mouse, termed RIG-ImScar, that enables fluorescence imaging and tractable immunoprecipitation of RIG-I in vivo. These mice revealed enrichment of RIG-I expression in circulatory, lymphoid, and mucosal tissues and broad expression across immune cell types. RIG-I itself is upregulated in response to IFN. To distinguish RIG-I sentinel cells, which are programmed to express RIG-I at steady state, from IFN-responder cells, we crossed RIG-ImScar mice with Mx1GFP mice. Blocking IFNAR with a monoclonal antibody showed that basal RIG-I expression in immune cells was largely independent of type I IFN signaling, although Ly6Chi monocytes required IFNAR for RIG-I expression. To probe functional responses in vivo, we intranasally administered a RIG-I-specific agonist, SLR14. Mapping RIG-I expression across the lung identified alveolar macrophages as a critical RIG-I sensor cell population, and depletion of alveolar macrophages, but not neutrophils, slightly impaired lung IFN responses. Together, these findings support the use of the RIG-ImScar model to probe RIG-I dynamics in vivo and predict functional sensor cell populations across tissues.

immunology↗