Researchers identified a mechanism that may be responsible for the toxic gain of function of Z-AAT, the most common form of alpha-1 antitrypsin (AAT) causing AAT deficiency (AATD), and published their results in JCI Insights.
“The findings of this study will contribute to elucidating more details in the pathogenesis of Z-AAT-associated lung diseases,” they wrote. “Therefore, the knowledge gained from this study may have significant implications for future therapeutic strategies for chronic airway inflammation in AATD individuals.”
AAT plays a critical role in maintaining lung homeostasis. People who are homozygous for the Z allele of the SERPINA1 gene produce very low levels of AAT, which is essential for the protection of the lungs from neutrophil elastase.
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Read more about the etiology of AATD
The exact mechanism of how Z-AAT leads to lung disease in AATD deficiency is not well understood. Researchers believe that the toxic gain-of-function effect of Z-AAT in macrophages may contribute to it.
Here, a team of researchers led by Mark Brantly, MD, showed that in Z-monocyte-derived macrophages toll-like receptor 7 (TLR7) signaling is activated and the expression level of NLRP3, which is a target of TLR7 signaling, is significantly higher.
The team also found that the level of endosomal Alu RNA, an endogenous ligand that activates TLR7 signaling, is significantly higher in Z-monocyte-derived macrophages.
The researchers concluded that Z-AAT “likely induces the expression of Alu elements” in monocyte-derived macrophages and accelerates the death of monocytes. This, they said, could be resulting in higher levels of endosomal Alu RNA in Z-monocyte-derived macrophages, which activates the TLR7 signaling and the expression of inflammatory molecules such as NLRP3, CXCL8, and TNF-alpha.
Reference
Lee J, Mohammad N, Lu Y, Kang K, Han K, Brantly M. Alu RNA induces NLRP3 expression through TLR7 activation in α-1-antitrypsin-deficient macrophages. JCI Insight. 2022;22;7(12):e158791. doi:10.1172/jci.insight.158791
