Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice

Abstract

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.

Molecular Profiling of the Hippocampus of Children with Autism Spectrum Disorder

“…These changes consisted of altered expression of ECMs involved in neurodevelopmental and synaptic regulation, including increased expression of the CSPG sulfotransferase CSGALNACT1 in microglia, and increased expression of the endogenous CSPG proteases MMP16 and ADAMTS9 17 . Furthermore, microglial signaling through the IL1RL1 receptor regulates hippocamal synaptic plasticity through ECM remodeling 93 , providing further support tha neurommune signaling molecules altered in children with ASD may impact ECM and synaptic molecules. Altered neuroimmune signaling thus may be at the intersection of immune signaling, synaptic plasticity and neurodevelopmental processes in the hippocampus of children with ASD.…”

“…Several genes with significantly increased expression in our study have recently been implicated in astrocyte response to inflammation, including CXCL10, GBP2, TIMP1, SPERPINA3 89 . Several of these molecules including CXCL10, TIMP1 and well as IL1RL1 have been demonstrated to impact synaptic plasticity [90][91][92][93] . ECMs are intricately involved with neuroimmune signaling in the regulation of neurodevelopmental processes and synaptic plasticity.…”

Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

“…42 Also, in the mouse spinal cord and thalamus, astrocyte secretion of IL-33 stimulates microglia to upregulate phagocytic pathways to engulf and remove synapses. [4][5][6] These studies indicate intercellular crosstalk between astrocytes and microglia occurs to coordinate synapse engulfment. However, the "eat-me" signals thought to tag synapses for elimination (e.g.…”

Microglia: Activity‐dependent regulators of neural circuits

“…Each of the studies used a different experimental paradigm to elicit elevated activity in the hippocampus, thus it could be that cell-type specific IL-33 production is sensitive to the pattern of activity. Although it is less clear if neural activity is involved, another important consideration is that in a developmental context, astrocyte-derived IL-33 appears to induce microglial phagocytic transcriptional programs via IL1RL1/ST2 to facilitate microglial elimination of synapses [26][27][28] (Figure 1B). How would the same molecule elicit seemingly opposing effects on synapses depending on the age of the animal?…”