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.
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.
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