Sensory neuronal mTORC1 signaling establishes neuroimmune memory that initiates allergic immunity

Keywords

• Allergy

• Sensory neurons

• Protease allergens

• Neuroimmune memory

• mTORC1

Main Findings

Protease allergens, which include papain and house dust mite (HDM), generate a TH2 cell-mediated immune response, and directly activate sensory neurons in the skin, resulting in substance P release and itch. Prior studies have shown that sensory neuronal SP promotes migration of CD301b+ PDL2+ (TH2-skewing), but not CD103+ XCR1+ (TH1-skewing) dendritic cells (DCs) from the skin to the draining lymph node (dLN) following allergen exposure, promoting a TH2 response. While the acute allergic response is well-characterized, how repeated sub-threshold exposures lead to subsequent sensitization remains unknown. In this preprint (not peer reviewed), Zhu et al. show that protease allergens induce mTORC1 signalling and mitochondrial remodelling in sensory neurons, promoting protease allergen sensitization and cross-sensitization.

Mice were injected intradermally with Pap or ovalbumin (OVA). Re-exposure to Pap after one week resulted in increased scratching, migration of TH2-skewing DCs to the dLN, and TH2 differentiation of CD4 T-cells. Scratching was not observed after exposure to heat-inactivated papain following Pap priming, suggesting that the phenotype is protease- but not antigenic-sequence-dependent. Pharmacologic blockade of sensory neurons during the first Pap exposure abrogated this response, but depletion of T-cells, B-cells, and mast cells/basophils did not, suggesting that sensory neuronal activation during the first exposure is required to develop neuroimmune memory.

Bulk RNA sequencing on sensory neurons showed Pap-induced mTORC1 upregulation, and both genetic and pharmacologic mTORC1 inhibition prevented sensitization without altering acute itch. Conversely, Nav1.8-specific heterozygous deletion of Tsc1, an endogenous mTORC1 inhibitor, increased scratching and TH2-skewing DC migration to dLN after single-dose Pap, phenocopying the trained response to Pap. Pap exposure also increased sensory neuronal mitochondrial size, branch length, DNA copy number, and PGC-1α, an mTORC1 target and regulator of oxidative metabolism and mitochondrial biogenesis.

Because increased itch upon re-exposure likely reflects protease activity and not antigen recognition, the authors evaluated cross-sensitization. Mice primed with sub-threshold HDM or Pap and then challenged with HDM exhibited increased itch, TH2-skewing DC migration, and TH2 differentiation. Cross-sensitization from Pap to HDM was lost with pharmacologic mTORC1 inhibition and in Tfam haploinsufficient mice with destabilized mitochondria.

Limitations

• Bulk RNAseq was only pursued in trigeminal ganglia, which do not provide sensory innervation to the majority of the skin. The analysis could benefit from a repeat in dorsal root ganglia.

• Experiments were conducted over 7-9 days; to confirm this is a memory phenotype, a longer timeframe would help.

Significance/Novelty

The findings of this preprint provide a fundamental shift in our understanding of allergy, extending it beyond immune hypersensitivity to a true neural hypersensitivity response.

Credit

Reviewed by Frederika Rentzeperis as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.