IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation

Abstract

Certain proteases derived from house dust mites and plants are considered to trigger initiation of allergic airway inflammation by disrupting tight junctions between epithelial cells. It is known that inhalation of proteases such as house dust mite-derived Der p1 and/or papaya-derived papain caused airway eosinophilia in naïve mice and even in Rag-deficient mice that lack acquired immune cells such as T, B and NKT cells. In contrast, little is known regarding the possible involvement of proteases derived from Aspergillus species (fungal-associated proteases; FAP), which are ubiquitous saprophytic fungi in the environment, in the development of allergic airway eosinophilia. Here, we found that inhalation of FAP by naïve mice led to airway eosinophilia that was dependent on protease-activated receptor-2 (PAR2), but not TLR2 and TLR4. Those findings suggest that the protease activity of FAP, but not endotoxins in FAP, are important in the setting. In addition, development of that eosinophilia was mediated by innate immune cells (ILCs) such as innate lymphoid cells, but not by acquired immune cells such as T, B and NKT cells. Whereas IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) are involved in induction of FAP-induced ILC-mediated airway eosinophilia, IL-33—rather than IL-25 and/or TSLP—was critical for the eosinophilia in our model. Our findings improve our understanding of the molecular mechanisms involved in induction of airway inflammation by FAP.

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

“…While IL‐33 is important for the development of bmILC2, other cytokines such as IL‐25 and TSLP have been shown to also be important for ILC2 in vivo . Furthermore, IL‐2 is important in stimulating IL‐5 and IL‐13 production by ILC2 .…”

“…While IL-33 is important for the development of bmILC2, other cytokines such as IL-25 and TSLP have been shown to also be important for ILC2 in vivo. [29][30][31] Furthermore, IL-2 is important in stimulating IL-5 and IL-13 production by ILC2. 32 When bmILC2 were stimulated with IL-2, IL7, IL-25, IL-33, and TSLP, there was now no difference in the frequency of cytokineproducing bmILC2 from RAG1 −/− and PD1xRAG1 −/− (Figure 7A,B).…”

Endocrine Disruptor Bisphenol A (BPA) Triggers Systemic Para-Inflammation and is Sufficient to Induce Airway Allergic Sensitization in Mice

“…Multiple lines of evidence point to the causality of epithelial barrier dysfunction in the development of allergic inflammation. A number of mouse and human models using protease epithelial damage triggers or the targeted deletion of structural or junctional barrier genes report enhanced allergic sensitization and Th2 inflammation [6][7][8][9]. Although research shows that exogenous proteases in many allergens themselves are sufficient to disrupt epithelium, this does not explain why only a fraction of the population exposed to the same allergens develops sensitization.…”

The Fungal Microbiome and Asthma

“…As previously mentioned, proteases are a unique feature of fungi that contribute to the pathology of fungi-associated asthma, and these enzymes in turn contribute to the specific immunological mechanisms induced in response to fungal airway exposure. Inhaled Aspergillus-derived fungal associated proteases (FAP) induced airway eosinophilia in naive mice through protease activated receptor-2 (PAR-2), indicating that this is directly associated with protease activity rather than sensitization (Hiraishi et al, 2018). IL-33 induced by PAR-2 signaling played a crucial role in this response through activation of ILC2 (independent of adaptive immunity) to drive the eosinophilic inflammation seen ( Figure 3B) (Hiraishi et al, FIGURE 4 | The gut-lung crosstalk in airway inflammation.…”