AUTHOR=Krysko Olga , Korsakova Darya , Teufelberger Andrea , De Meyer Amse , Steels Jill , De Ruyck Natalie , van Ovost Judith , Van Nevel Sharon , Holtappels Gabriele , Coppieters Frauke , Ivanchenko Mikhail , Braun Harald , Vedunova Maria , Krysko Dmitri V. , Bachert Claus TITLE=Differential protease content of mast cells and the processing of IL-33 in Alternaria alternata induced allergic airway inflammation in mice JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1040493 DOI=10.3389/fimmu.2023.1040493 ISSN=1664-3224 ABSTRACT=Background

Recent in vitro studies strongly implicated mast cell-derived proteases as regulators of IL-33 activity by enzymatic cleavage in its central domain. A better understanding of the role of mast cell proteases on IL-33 activity in vivo is needed. We aimed to compare the expression of mast cell proteases in C57BL/6 and BALB/c mice, their role in the cleavage of IL-33 cytokine, and their contribution to allergic airway inflammation.

Results

In vitro, full-length IL-33 protein was efficiently degraded by mast cell supernatants of BALB/c mice in contrast to the mast cell supernatants from C57BL/6 mice. RNAseq analysis indicated major differences in the gene expression profiles of bone marrow-derived mast cells from C57BL/6 and BALB/c mice. In Alternaria alternata (Alt) - treated C57BL/6 mice the full-length form of IL-33 was mainly present, while in BALB/c mice, the processed shorter form of IL-33 was more prominent. The observed cleavage pattern of IL-33 was associated with a nearly complete lack of mast cells and their proteases in the lungs of C57BL/6 mice. While most inflammatory cells were similarly increased in Alt-treated C57BL/6 and BALB/c mice, C57BL/6 mice had significantly more eosinophils in the bronchoalveolar lavage fluid and IL-5 protein levels in their lungs than BALB/c mice.

Conclusion

Our study demonstrates that lung mast cells differ in number and protease content between the two tested mouse strains and could affect the processing of IL-33 and inflammatory outcome of Alt -induced airway inflammation. We suggest that mast cells and their proteases play a regulatory role in IL-33-induced lung inflammation by limiting its proinflammatory effect via the IL-33/ST2 signaling pathway.