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IL-33/ERK Signaling Promotes Neural Repair by Driving Functional Microglial Renewal

ABSTRACT: Repair after central nervous system injury depends on remodeling of the immune microenvironment, in which microglial regeneration is critical. Here, we found that IL-33 promotes microglial regeneration through IL1RL1/ST2–ERK signaling and induces a reparative, inflammation-resolving phenotype characterized by high expression of TREM2, IGF1, TGF-β, and IL-10, and low expression of TNF-α, IL-1β, CD86, and FcγRIII. These newly generated microglia displayed enhanced phagocytic activity and lysosomal activation, reshaped cell–cell communication networks, and promoted hippocampal neurogenesis, synaptic repair, axonal regeneration, and cognitive recovery. IL1RL1 knockdown, ERK inhibition, or microglial depletion weakened the restorative effects of IL-33. Connectivity Map screening further identified curcumin as an IL-33-mimetic compound that promoted microglial renewal and phagocytosis both in vivo and in vitro. In a carbon monoxide poisoning model, CO exposure suppressed the expansion of proliferative microglial subsets and ERK phosphorylation, leading to impaired functional regeneration. Together, these findings suggest that the IL-33/IL1RL1–ERK axis promotes neural repair by inducing pro-efferocytic, low-inflammatory regenerative microglia, providing a potential immunomodulatory strategy for toxic brain injury.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Xudong Zhou

LAB HEAD: Xudong Zhou

PROVIDER: PXD078972 | Pride | 2026-08-03

REPOSITORIES: Pride

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