# Neuronally-driven accumulation of glycolytic MafB+MHCIIhi IMs drive airway allergy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $629,984

## Abstract

ABSTRACT
Dysregulated Th2 responses are central to the pathogenesis of allergic diseases. The central dogma is that
classical dendritic cells (cDCs) are the primary drivers of Th2 cells, this has been largely established using
strategies targeting CD11c, which while expressed by cDCs, is also present by other cells like monocytes and
macrophages. Our data demonstrates the existence of population of MafB+CD11c+MHCIIhi interstitial
macrophages (MHCIIhi IMs), significantly induced in response to house dust mite (HDM). Thus, previous
strategies aimed at cDCs may have co-targeted these IMs. Using specific targeting, we show for the first time
that these MHCIIhi IMs are central to driving allergen-induced Th2 responses in the airways. Our data propose
that the development of Th2 immunity, which has long been the purview of dendritic cells, now includes a central
role for MHCIIhi IMs. Consistently, we also find that HLA-DRhi macrophages are elevated in the tissue of patients
with allergic nasal polyps. Although their regulation during allergy is not understood. Using chemogenetic
approaches, we find that pulmonary innervation emanating from the vagal ganglia (VG) directly induces MHCIIhi
IM accumulation during HDM-induced allergic airway inflammation, strongly indicating that VG neurons
contribute to IM accumulation in response to allergen. Therefore, vagal ganglion-neuropeptide-IM crosstalk acts
as a potential axis mediating airway allergy. Exploring the bioenergetics of these cells, we find that MHCIIhi IMs
appear to rely heavily on glucose metabolism for function. They express the highest levels of glycolysis-
associated genes, and impairing glucose metabolism decreases their ability to take up HDM, something not seen
in cDCs in vivo, suggesting that IMs are intrinsically different than cDCs in their reliance on glycolysis for antigen-
presenting function. Further, blocking glycolysis reduces eosinophils, Th2 cells, and IgE, but not neutrophils,
cDCs, or IL-13+ILCs. Lastly, we found that HDM-elicited MHCIIhi IMs are also highly enriched for arginase-1, a
canonical marker of M2 macs, more so than any other myeloid cell type, including AMs. We postulate that innate
cytokines act as microenvironmental signals that condition IMs, favoring the development of Th2 cells. Seeking
to understand this mechanism, we found that IMs express high levels of the IL-33 receptor, ST2 and eliminating
IL-33 signaling impacts arg1+IMs, but not total IMs. Moreover, we found that neuronal inputs induce ST2
expression, thus sensitizing macs to IL-33. In sum, we hypothesize that HDM-elicited IL-33 promotes an M2-like
polarization state, favoring an MHCIIhi IM-T cell dialog that drive Th2 responses. To examine this, we propose
to: 1) Examine the neuronal pathways regulating MHCIIhi IM accumulation, 2) Examine the glycolytic program of
MHCIIhi IMs, and test its requirement for Th2 responses, 3) test neuropeptide-IL-33 axis that drives alternative
MHCIIhi IMs polarization favori...

## Key facts

- **NIH application ID:** 10873291
- **Project number:** 5R01AI170709-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Stephane Lajoie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $629,984
- **Award type:** 5
- **Project period:** 2023-06-21 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873291

## Citation

> US National Institutes of Health, RePORTER application 10873291, Neuronally-driven accumulation of glycolytic MafB+MHCIIhi IMs drive airway allergy (5R01AI170709-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873291. Licensed CC0.

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