Hematopoietic 12/15-lipoxygenase activity negatively contributes to fungal-associated allergic asthma

Autor: Mgayya Makullah, Diandra A. Ellis, MaryJane Jones, Chad Steele
Rok vydání: 2023
Předmět:
Zdroj: American Journal of Physiology-Lung Cellular and Molecular Physiology.
ISSN: 1522-1504
1040-0605
DOI: 10.1152/ajplung.00090.2023
Popis: Asthma is one of the most common non-communicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with allergy to the opportunistic mold Aspergillus fumigatus. Leukotrienes, immunopathogenic mediators derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe asthma. As such, these mediators are FDA-approved therapeutic targets of the anti-asthmatic drugs Zileuton®/Zyflo® and Singulair®/Montelukast®. A second enzyme involved in AA metabolism is 12/15-lipoxygenase (12/15-LOX; Alox15). Here, C57BL/6 wild-type mice subjected to experimental fungal asthma had increased expression of Alox15 mRNA as well as increased levels of 12-HETE, a product of 12/15-LOX activity, in the lung when compared to naïve and vehicle-treated mice. Mice deficient in 12/15-LOX ( Alox15-/-) demonstrated better lung function, as measured by airway hyperresponsiveness (AHR), during fungal asthma. Histological assessment revealed reduced inflammation in the lungs of Alox15-/- mice compared to WT mice, which was corroborated by flow cytometric analysis of multiple myeloid (eosinophils, neutrophils) and lymphoid (CD4+ T, γδ T) cell populations. This was further supported by decreased levels of specific chemokines that promote the recruitment of these cells. Likewise, type 1 and 2, but not type 17 cytokines, were significantly lower in the lungs of Alox15-/- mice. Bone marrow chimera studies revealed that the presence of 12/15-LOX in hematopoietic cells contributed to AHR during fungal asthma. Taken together, our data supports the hypothesis that hematopoietic-associated 12/15-LOX contributes to type 2 responses and exacerbation of allergic fungal asthma.
Databáze: OpenAIRE
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