IL-33 as a boundary-tissue state-transfer signal: a Reader-Alarmin-Effector architecture linking CNS and skin

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 reactive gliosis and matrix deposition also occur in pathological contexts. In skin, short-lived suprabasal keratinocytes may transfer inflammatory information to longer-lived carriers, including basal and bulge stem cells, Langerhans cells, tissue-resident memory T cells, mast cells, and sensory afferents; this handoff could favour additive remodelling such as hyperinnervation, cellular accumulation, and matrix deposition. This turnover asymmetry motivates a three-threshold working model of chronicity - effector activation, reader reprogramming, and structural persistence - that is presented as experimentally separable layers rather than an obligatory temporal sequence. The model generates testable predictions for single-cell and spatial profiling and links CNS synaptic set-points with chronic itch and sensory amplification within a shared brain-behavior-immunity framework.