Ficolin-A Protects Against Allergic Asthma via Suppressing ILC2-Drived Type 2 Inflammation

Type 2 inflammation has emerged as a pivotal mechanism for asthma, which involves both innate and adaptive immunity. Human ficolin (FCN)-2 (L-ficolin, P35) and its mouse homolog FCN-A are one of the major pattern recognition molecules of plasma/serum, acting as important initiators of the lectin complement system and playing important roles in immunity, including respiratory immunity. However, little is known about the role of FCN-2/A in allergic asthma.

Serum FCN-2 and IgE levels in 90 allergic asthmatic patients and 48 healthy controls were measured by ELISA. Aeroallergen house dust mite (HDM)-induced mouse model of asthma was generated in both wild type (WT) and FCN-A knockout (KO) mice. Mouse serum and bronchoalveolar lavage fluid (BALF) IgE levels, lung innate lymphoid cells (ILC)1/2/3, the expression of transcription factors GATA3, T-bet, and RORγt, and the concentrations of type 2 cytokines in serum and BALF were measured by FCM, RT-qPCR, Western blot, and ELISA.

Serum FCN-2 concentrations in patients with allergic asthma were significantly lower than those in healthy controls. Similarly, lower serum and BALF FCN-A concentrations were observed in HDM-induced asthma mouse models compared to those of uninduced mice. In the asthma mouse model, FCN-A KO asthmatic mice had higher levels of total IgE and HDM-specific IgE (sIgE), β-hexosaminidase (β-HEX) and histamine secretion, as well as increased airway epithelial permeability with the release of FITC-dextran in sera, inflammatory cell infiltration and eosinophil counts, and displayed more severe disease symptoms with histological damage compared to WT asthmatic mice. FCN-A KO asthmatic mice showed decreased T-bet⁺ ILC1 and increased IL-5⁺/IL-13⁺ ILC2/ILC2 proportions, p-GATA3 expression, serum and BALF type 2 cytokines IL-4, IL-5, and IL-13, Th17 cytokine IL-17, and chemokines CCL2/4 production. Importantly, the administration of exogenous FCN-A protected against mouse allergic airway inflammation with decreased ILC2 proportions and type 2 cytokines expression, serum total and allergen-specific IgE production. These results suggest that FCN-A suppresses both ILC2 innate immunity and IgE-mediated adaptive immunity during asthma.

Our findings provide previously unreported evidence that FCN-A protects against allergic asthma by suppressing lung ILC2-driven type 2 inflammation.