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Myeloid PKM2 deficiency alleviates allergic airway inflammation and promotes macrophage efferocytosis via SLC13A3
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DOI：10.1007/s00011-026-02329-z.png)
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Abstract
En 中文
Allergic asthma is characterized by chronic airway inflammation that fails to resolve efficiently. Defective efferocytosis and metabolic reprogramming of macrophages are crucial factors in allergic diseases. While PKM2 is known to participate in phagocytosis and metabolism, its specific role in modulating asthma remains unclear. To delineate the underlying mechanisms of PKM2 in allergic asthma. We generated myeloid cell-specific LysMcrePKM2fl/fl mice, with littermate PKM2fl/fl mice serving as controls, and challenged them with ovalbumin (OVA) extract to induce allergic airway inflammation. In vivo, we assessed airway hyperresponsiveness, pulmonary inflammation, Th2 cytokine levels, apoptosis, and efferocytosis-related receptor expression. Primary bone marrow-derived macrophages(BMDMs) were isolated for in vitro evaluation of efferocytic activity under distinct polarization conditions. To investigate underlying mechanisms, we performed RNA-seq to identify PKM2 downstream targets, followed by lentiviral-mediated overexpression of the candidate molecule SLC13A3 in THP-1 cells, with validation through molecular docking, immunoprecipitation, and functional assays. We found that PKM2 is upregulated in macrophages during asthma. Myeloid cell-specific PKM2 deficiency mitigated OVA-induced Th2 inflammation and eosinophilic apoptosis while reducing airway hyperresponsiveness (AHR). Mechanistically, PKM2-expressing macrophages exhibited decreased SLC13A3 transcription, which drove activation of the PI3K-AKT and redistributed STAT6/1 ratio to impair efferocytosis. This impairment disturbed the M2/M1 balance. In vitro experiments confirmed that SLC13A3 overexpression enhanced efferocytic capacity and promoted a shift toward M2/M1 balance. Conversely, PKM2 overexpression in macrophages impaired efferocytosis and exacerbated chronic airway inflammation. Our study reveals a novel role for myeloid cell-specific PKM2 and SLC13A3 in asthma, linking efferocytosis to immune metabolism during allergic inflammation.
Keywords:
PKM2
Efferocytosis
SLC13A3
Macrophage polarization
Allergic inflammation
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