Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency

Abstract

The hereditary disorder α-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-κB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease–anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.

Dysregulation of TIM-3–Galectin-9 Pathway in the Cystic Fibrosis Airways

“…5A). Because BAL fluid is considered to be from 25-to 100-fold diluted compared with epithelial lining fluid (39,44), these values indicate that galectin-9 can be present in the nanomolar range on the lung surface in vivo in conditions with a marked neutrophilic component such as COPD or non-CF bronchiectasis, but not in adult CF.…”

Measurement of the Unfolded Protein Response (UPR) in Monocytes

“…Monocytes from cystic fibrosis (CF) patients were shown to be intrinsically abnormal in their cytokine responses (Zaman et al, 2004), but this can be reversed by inhibitors designed to prevent ∆F508 CFTR (cystic fibrosis transmembrane conductance regulator) degradation by ERAD and increase the secretion of CFTR (Vij et al, 2006). In addition, work from this group has demonstrated intracellular accumulation of Z alpha-1 antitrypsin (AAT) in the ER of monocytes, and this causes sustained activation of the UPR with subsequent effects on immune function (Carroll et al, 2010).…”

“…For example, we have used this technique to show impaired secretion of AAT from monocytes isolated from alpha-1 antitrypsin deficient-individuals (Carroll et al, 2010).…”

“…For example, we have used this technique to show intracellular accumulation of AAT within the ER of monocytes from alpha-1 antitrypsin deficient-individuals, as well as increased GRP78 and GRP94 expression (Carroll et al, 2010).…”

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

“…In contrast to hepatocytes, Z-AAT induces UPR in monocytes where its expression is low [ 124 ]. Thus, in different proteostasis environments in which the aggregation phenotype may be reduced because of a smaller load of Z-AAT nasce nt chain whose polymer propensity is logarithmically proportional to concentration like amyloid, Z-AAT folding species may be suffi ciently long-lived to be preferentially targeted to G/ERAD pathways [ 92 ].…”