Cryo-EM structures reveal how the IL-36 receptor switches on inflammation

Researchers at VIB and Ghent University have determined how the IL-36 receptor, a key driver of inflammation, is activated at the molecular level. Their cryo-electron microscopy study, published in Science Immunology, shows that signalling depends on how the components assemble rather than on how tightly the first molecule binds. The work also clarifies how spesolimab, an antibody used for a severe form of psoriasis, shuts the pathway down.

A weak first contact, then a tight complex

The IL-36 receptor helps cells respond to inflammatory signals. Inflammation is a necessary defence against infection and injury, but excessive or poorly controlled signalling contributes to diseases such as psoriasis.

The team, led by Dr Danielle Clancy and Professor Savvas Savvides at the VIB-UGent Center for Inflammation Research, used the VIB-VUB cryo-electron microscope. The technique visualises biological molecules at near-atomic resolution, and it allowed the researchers to capture the assembled machinery around the receptor that generates an inflammatory signal.

The inflammatory molecule IL-36γ binds the receptor only relatively weakly at first. That initial contact, however, allows a further receptor component to join far more tightly, forming a stable complex capable of driving a strong response. First author Dr Julie Andries noted that one might expect the strongest signal to arise from the tightest interaction, but the structures show otherwise: the way the pieces come together determines how effectively the signal is passed on.

IL-37 shows the opposite pattern

The researchers also examined IL-37, a related immune molecule. It attaches to the IL-36 receptor much more strongly than IL-36γ does, yet it is less able to complete the signalling complex. The result is a weaker inflammatory response.

This comparison illustrates that different molecules can use the same receptor in distinct ways. According to Clancy, binding to a receptor is only part of what triggers inflammation, and these differences can substantially affect the outcome.

How spesolimab blocks the signal

The structures also shed light on spesolimab. One might assume that an antibody would simply cover the site where IL-36γ binds. Instead, spesolimab engages the IL-36 receptor at a different location. This causes an unexpected restructuring of the receptor, which prevents IL-36γ from engaging with it and so halts the inflammatory signal.

Savvides described the findings as showing both how the signal is switched on and how it can be switched off. For antibody design, the result is a reminder that effective inhibitors need not compete directly at the binding site; they can act by altering the receptor's shape.

Why it matters and what comes next

The source describes the study as a structural blueprint rather than a clinical advance. The structures give researchers defined rules for when signalling through this receptor becomes strong, weak or blocked. These rules can guide studies of the IL-36 pathway in other inflammatory conditions and inform work on more selective ways of targeting it.

Several questions remain open. The report does not describe tests of new therapeutic candidates, and the structures alone do not show how the pathway behaves across different tissues or diseases. Those questions will need functional and clinical studies built on the structural framework now available.

The paper is Andries et al., “The structural basis of IL-36R proinflammatory signaling mediated by IL-36γ and IL-37”, Science Immunology (2026).

Source: An inside look at a molecular switch that triggers inflammation (Medical Xpress, 10 November 2026).

Image: AI-generated illustration.