Biology subjects

Capon, F.

Publications and source records attributed to Capon, F..

3 recordsLinked to original sources

bioRxiv2025

IL-36γ signalling promotes a proinflammatory macrophage state that is associated with reduced lipid uptake

Macrophages exhibit remarkable functional plasticity, adopting immune activating or immune suppressive states in response to environmental cues. While these phenotypic shifts are essential to immune homeostasis, the mechanisms whereby they are regulated in humans are poorly understood. Here, we investigated the role of interleukin (IL)-36{gamma}, a barrier cytokine that is strongly induced in response to infection. We show that IL-36{gamma} signalling modifies the anti-inflammatory phenotype of human alternatively activated (M2a) macrophages, by decreasing the expression the CD163 M2 marker. This change was accompanied by the upregulation of M1 surface markers (CD40, CD80) and M1 cytokines (e.g. TNF, CXCL8). IL-36{gamma} treatment of M2a macrophages also reduced the expression of TREM2 and CD36, two lipid-binding receptors that sustain the energy requirements of the M2 state. Accordingly, we also observed a decrease in the uptake of CD36 and TREM2 ligands (oxidised low-density lipoproteins). These findings indicate that IL-36{gamma} shifts the immune and metabolic profile of M2a macrophages towards an M1-like state.

immunology↗

bioRxiv2025

Interleukin-36 upregulates type-I interferon responses in systemic lupus erythematosus by promoting the accumulation of self-nucleic acids

IntroductionSeveral studies have reported an up-regulation of interleukin (IL)-36 in the serum of patients with systemic lupus erythematosus (SLE). Here, we sought to define the mechanisms whereby IL-36 may contribute to the over-activation of type I Interferon (IFN) responses observed in SLE. MethodsWe carried out single-cell (sc)RNA-seq in healthy peripheral blood mononuclear cells treated with IL-36 (n=5 donors). We compared the genes and transcriptional networks that were induced by IL-36 with those that were upregulated in a published SLE scRNA-seq dataset (n=33 cases and 11 controls). In follow-up studies, we validated the effects of IL-36 on monocytes by real-time PCR (n=9 donors) and flow-cytometry (n=6). ResultsClassical monocytes were the immune population most affected by IL-36 treatment (n=203 Differentially Expressed Genes). In these cells, IL-36 upregulated transcriptional networks (regulons) driven by IRF7, a key activator of type I IFN responses. A similar upregulation of IRF7 regulons was observed in the monocytes of SLE cases, where measurements of IL-36 and IRF7 activity were significantly correlated (r=0.35, P=0.02). Experimental follow-up studies in human monocytes showed that IL-36 downregulates multiple RNAse genes (RNASE1, RNASE6, RNASET2). IL-36 treatment of monocytes also increased the percentage of apoptotic cells (45% vs 37% in untreated cells; P=0.001), which are a critical source of self-nucleic acids. ConclusionWe find that IL-36 promotes monocyte apoptosis while downregulating self-nucleic acid clearance. Thus, IL-36 contributes to the accumulation of self-nucleic acids, a key driver of type I IFN responses in SLE.

immunology↗

bioRxiv2018

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. Both chronic and acute forms of the disease are characterised by abnormal interleukin (IL)-36 signalling. While the mechanisms whereby IL-36 promotes cutaneous inflammation are well established, its systemic effects have not been investigated. To address this issue, we initially measured leukocyte gene expression in generalised pustular psoriasis, an acute disease variant caused by mutations of the IL-36 receptor antagonist. By undertaking whole-blood and neutrophil RNA-sequencing in affected individuals, we identified a Type-I IFN signature, which correlated with IL-36 signalling up-regulation. We then validated these observations in patients with chronic plaque psoriasis. Finally, we demonstrated that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates Toll-like Receptor (TLR)-9 activation and IFN production. This effect was mediated by the induction of PLSCR1, an endosomal TLR-9 transporter. These results define an IL-36/TLR-9/Type-I IFN axis that could be targeted for the treatment of psoriasis co-morbidities.

immunology↗