IL-33 as a boundary-tissue state-transfer signal: a Reader-Alarmin-Effector architecture linking CNS and skin
Abstract
Interleukin-33 (IL-33) is recognised both as an epithelial alarmin in type 2 barrier inflammation and as an astrocyte-, neuron-, and microglial-linked signal that licenses synapse and extracellular-matrix remodelling in the central nervous system (CNS). These two literatures have largely developed in parallel despite a shared logic: in both settings, a tissue-resident structural cell senses local stress, mobilises a nuclear alarmin, and instructs a resident ST2-responsive effector compartment to remodel the local niche. Here I propose a Reader-Alarmin-Effector framework for IL-33 biology at boundary tissues. Astrocytes and keratinocytes are not treated as equivalent cell types but as functionally convergent Readers: resident stress-integrating cells positioned to convert local disturbance into niche-level state change. Microglia in the CNS and a mast-cell-centred ST2-responsive effector field in skin provide parallel, but non-identical, Effector modules; recent evidence indicates that the CNS Reader-Effector relationship is reciprocal, with microglial ST2 signalling driving amphiregulin production that feeds back onto astrocytic EGFR (Wheeler et al., 2023). The framework may help explain why a similar IL-33-centred architecture is associated with divergent tissue outputs. In the CNS, the relative longevity of Reader and Effector cells may permit more cell-autonomous storage of inflammatory state and favour subtractive remodelling such as synaptic refinement, although…
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