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bioRxiv · 10.1101/2025.10.22.683795

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

Sieh, J. Y. X.·Osborn, G.·Karagiannis, S.·Capon, F.
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Abstract

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.

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Sieh, J. Y. X., Osborn, G., Karagiannis, S., Capon, F.. 2025-10-23. IL-36γ signalling promotes a proinflammatory macrophage state that is associated with reduced lipid uptake. https://doi.org/10.1101/2025.10.22.683795

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