The role of intranasal Arginase-1 therapy on myeloid-derived suppressor cells in a murine model of asthma
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Abstract
Asthma is a chronic inflammatory disease of the lower airways characterized by airway obstruction, hyperresponsiveness, and heterogeneous inflammatory endotypes. While Type-2-high asthma is driven primarily by Th2-mediated allergic inflammation, Type-2-low asthma remains a clinically challenging endotype with poor response to inhaled corticosteroids and limited therapeutic options. Myeloid-derived suppressor cells have emerged as potent regulators of immune responses in a variety of inflammatory diseases. Their immunosuppressive function largely relies on L-arginine depletion via Arginase-1. Previous work from our group demonstrated that increasing myeloid-derived suppressor cell activity using a Prostaglandin E2 receptor 4 agonist or intravenous Arginase-1 ameliorates airway inflammation in murine models of asthma. Building on these findings, this project investigates whether local Arginase-1 delivery through intranasal administration can reproduce or even enhance the beneficial effects observed after systemic treatment. Using a validated two-week house dust mite extract exposure protocol, mice received intranasal Arginase-1 at two doses (10 or 20 mg/kg bodyweight) during the second week of sensitization. Three days after the final treatment, airway mechanics were assessed under increasing doses of methacholine, followed by detailed immunological and histopathological characterization. These included bronchoalveolar lavage fluid cytology, histological analysis of lung tissue, quantification of pulmonary and splenic CD4⁺ T-cell subsets, and ex vivo analysis of myeloid-derived suppressor cells’ activity.
House dust mite extract exposure induced classical inflammatory changes and goblet cell hyperplasia, although the overall phenotype was mild. Intranasal administration of Arginase-1 did not improve airway hyperresponsiveness. In fact, Arginase-1-treated asthmatic mice showed a slight, non-significant increase in airway resistance. Elastance-related parameters remained largely unchanged. The higher dose of Arg1 did not yield increased efficacy. Intranasal Arginase-1 therapy did not reduce inflammatory scores or eosinophilia in bronchoalveolar lavage fluid. Goblet cell numbers and perivascular inflammation were slightly elevated compared to healthy controls but comparable to untreated asthmatic mice. While exposure to house dust mite extract alone did not significantly alter T-cell populations in lungs or spleen, Arginase-1 treatment at 20 mg/kg produced a modest reduction in Th1, Th17, activated CD4⁺ T cells, and regulatory T cells. The effect was more pronounced in the lungs and less marked in the spleen. Th2 cells were largely unaffected, consistent with known lower L-arginine dependence of Th2 cytokine production. Unlike intravenous Arginase-1, intranasal therapy did not increase Myeloid-derived suppressor cells numbers in lungs or spleen. Ex vivo assays revealed only a trend toward enhanced suppressive function of monocytic myeloid-derived suppressor cells, failing to reach statistical significance. Polymorphnuclear myeloid suppressor cells remained unaffected.
This thesis demonstrates that while Arginase-1 may have immunomodulatory potential, its effects depend on the route of administration and disease severity. Intranasal Arginase-1 was well tolerated but did not replicate the therapeutic benefits previously observed with intravenous treatment. Several mechanisms may explain this discrepancy:
• The mild HDM model used in the intranasal experiments may have been insufficient to reveal clear therapeutic effects, as inflammatory and physiological changes were generally modest.
• By affecting the L-arginine homeostasis in the lung and competing with other enzymes, mainly nitric oxide synthases, the beneficial effects of nitric oxide – mainly bronchodilation – may have been diminished by Arginase-1.
• Arginase-1 was able to mimic the effects of myeloid-derived suppressor cells but did not further impact their generation and suppressive activity.
Importantly, Arginase-1 preferentially reduced Th1-associated inflammation rather than classical Th2 pathways, suggesting potential relevance for treatment-resistant T2-low asthma. However, more robust models and refined delivery strategies are required to fully evaluate this therapeutic angle.
The work presented here provides a comprehensive assessment of intranasal Arginase-1 therapy in murine asthma. While the treatment proved safe and induced subtle immunological shifts, it did not significantly ameliorate airway physiology, inflammatory pathology, or myeloid-derived suppressor cell function in the acute house dust mite induced model. Follow-up experiments in chronic and exacerbation settings further underscored the limited efficacy of Arginase-1 when administered locally. These findings highlight the complexity of targeting L-arginine metabolism in asthma and emphasize the need for deeper mechanistic studies to optimize myeloid-derived suppressor cell-based or Arginase-1-driven therapeutic strategies.
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This item has been published with the following license: In Copyright