&lt;p&gt;Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency&lt;/p&gt;

Belchamber, Kylie; Walker, E. A.; Stockley, Robert A.; Sapey, Elizabeth

doi:10.2147/copd.s276792

Cited by 20 publications

(18 citation statements)

References 76 publications

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“…Both alveolar and monocyte-derived macrophages express and secrete AAT. Monocyte differentiation to macrophages has been shown to increase the expression level of AAT up to threefold [ 11 ]. In AATD, accumulation of misfolded ZAAT in monocytes and macrophages causes the unfolded protein response and activates NF-kb pathways and expression of pro-inflammatory cytokines [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency

et al. 2022

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Background Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. Methods Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is “cross talk” between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. Results AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. Conclusions The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.

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Section: Introductionmentioning

confidence: 99%

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency

et al. 2022

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“…The liver is the major producer of AAT, therefore the accumulation of Z-AAT polymers in hepatocytes is a marker for diagnosing AATD ( Janciauskiene et al, 2011 ). The intracellular Z-AAT polymers have also been identified in other AAT-expressing cells like monocytes and macrophages ( Belchamber et al, 2020 ). The accumulation of polymers is harmful for AAT-producing cells, whereas the circulating Z-AAT polymers are not able to execute the tasks of AAT protein, a major inhibitor of serine proteases having a strong immunomodulatory potential.…”

Section: Resultsmentioning

confidence: 99%

Polymerization of misfolded Z alpha-1 antitrypsin protein lowers CX3CR1 expression in human PBMCs

Tumpara

Ballmaier

Wrenger

et al. 2021

eLife

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The CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host`s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human PBMCs. This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.

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“…AATD causes a genetically driven loss of proteostasis with an accumulation of misfolded AAT in hepatocytes and macrophages, leading to low levels of functional AAT and cellular damage (Belchamber et al, 2020) due to endoplasmic reticulum (ER) stress responses. Patients with cystic fibrosis (CF) have a genetic dysfunction in the cystic fibrosis transmembrane regulator (CFTR) protein, leading to a decline in lung health, an increased susceptibility to infection, pancreatic dysfunction and infertility (Gibson et al, 2003).…”

Section: Why Do the Lungs Age And What Is The Evidence For The Hallma...mentioning

confidence: 99%

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

Faniyi

Hughes

Scott

et al. 2022

British J Pharmacology

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Lung diseases disproportionately affect elderly individuals. The lungs form a unique environment: a highly elastic organ with gaseous exchange requiring the closest proximity of inhaled air containing harmful agents and the circulating blood. The lungs are highly susceptible to senescence, with age and ‘inflammageing’ creating a pro‐inflammatory environment with a reduced capacity to deal with challenges. While lung diseases may have disparate causes, the burden of ageing and inflammation provides a common process that can exacerbate seemingly unrelated pathologies. However, these shared pathways may also provide a common route to treatment, with increased interest in drugs that target ageing processes across respiratory diseases. In this review, we will examine the evidence for the increased burden of lung disease in older adults, the structural and functional changes seen with advancing age and assess what our expanding knowledge of inflammation and ageing pathways could mean for the treatment of lung disease. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

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<p>Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency</p>

Cited by 20 publications

References 76 publications

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency

Polymerization of misfolded Z alpha-1 antitrypsin protein lowers CX3CR1 expression in human PBMCs

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

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