Advisor(s)

Beatriz Leon-Ruiz

Committee Member(s)

Andre Ballesteros-Tato
Casey Weaver
Robert Welner
Troy Randall

Document Type

Dissertation

Date of Award

1-27-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Allergens are non-infectious environmental proteins that can trigger T helper 2 (Th2) cell-mediated inflammation in atopic individuals. Allergens are structurally diverse and typically lack pathogen-associated molecules patterns (PAMPs), which are recognized by pathogen recognition receptors (PRRs). PRRs are the canonical sensors of the innate immune system that typically detect PAMPs in microbes, initiating signaling pathways that drive pathogen clearance. Because allergens generally do not activate PRRs in the same way as infectious agents, alternative detection mechanisms are likely responsible for their recognition and the subsequent initiation of Th2 cell-mediated inflammation. House Dust Mite (HDM), a major indoor allergen, and other allergens such as cockroach and fungal-derived allergens, contain intrinsic protease activity that has been implemented in promoting Th2 allergic responses. We demonstrate that the cysteine protease activity of the major HDM allergen Der p1, as well as similar protease activity from other allergens, including experimental models such as papain, is required for the generation of Th2 allergic inflammation. We further identify Protease Activated Receptor 2 (PAR2) as the sensor of this protease activity, expressed by a previously unrecognized airway macrophage, characterized by Ly6G and Nur77 (Nr4a) expression. These Ly6G+Nur77+ macrophages require both PAR2 and the transcription factor Nur77 for the detection of cysteine protease allergens and their accumulation in the airways, respectively. Upon activation, Ly6G+Nur77+ macrophages produce cysteinyl leukotrienes (cysLTs), which drive the migration of conventional dendritic cell (cDC) to the lung-draining mediastinal lymph node (LN). CysLTs enhance CCR7-mediated cDC migration by promoting chemotaxis towards CCL21, the CCR7 ligand expressed in afferent lymphatics. This facilitates the initial trafficking of cDCs to the LN, where they prime and expand allergen-specific T cells. Importantly, pharmacological inhibition of cysLT synthesis reduced cDC migration and diminished Th2 allergic responses. In summary, we identify a novel allergen-sensing airway macrophage that detects cysteine protease activity through PAR2, linking the recognition of allergens to the initiation of Th2 immunity. By promoting cDC migration through cysLT production, these macrophages act as an early orchestrator of the allergic cascade. Targeting the protease-sensing pathways and its downstream mediators offers promising opportunities for therapeutic intervention in allergic diseases.

Keywords

cysteinyl leukotrienes;dendritic cells;Ly6G+ macrophages;protease allergens;protease-activated receptor 2;Type 2 immunity

ProQuest Publication Number

32280897

ISBN

9798273381117

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