Background: Allergic asthma is a prevalent respiratory disease that has a significant impact on human health. Isthmin-1 (ISM1) is an endogenous anti-inflammatory protein downregulated in asthmatic lungs, but its role in allergic asthma remains unexplored.

Aim: To investigate the role of ISM1 in allergic airway inflammation.

Methods: We investigated the impact of ISM1 deficiency on airway inflammation using a house dust mite (HDM)-induced allergic asthma model in ISM1^-/- mice. We intratracheally delivered rISM1 to rescue the effects of ISM1^-/- in HDM-challenged mice. Molecular cell biology techniques were used to elucidate the underlying mechanisms.

Results: ISM1 functions to restrain airway hyperresponsiveness in allergic asthma in mice. ISM1^-/- mice showed an apparent worsening of allergic airway inflammation and hyperresponsiveness, accompanied by an increased HDM-specific IgE. The heightened inflammation in ISM1^-/- mice correlated with enhanced lung cell necroptosis, as indicated by higher pMLKL expression. Intratracheal delivery of rISM1 significantly reduced eosinophil number in BALF. Mechanistically, ISM1 stimulates adiponectin secretion by type 2 alveolar epithelial cells through the GRP78 receptor and enhances adiponectin-facilitated apoptotic cell clearance via alveolar macrophage efferocytosis. Reduced adiponectin expression under ISM1 deficiency also contributed to intensified necroptosis, prolonged inflammation, and heightened severity of airway hyperresponsiveness.

Conclusions: ISM1 downregulation in asthmatic lungs contributes to the progression of allergic asthma. Local airway-delivered rISM1 has therapeutic potential against allergic asthma and warrants further investigation.