Abstract
RationaleActivation state-dependent secretion of alpha-1 proteinase inhibitor (A1PI) by monocytes and macrophages was first reported in 1985. Since then, monocytes and tissue macrophages have emerged as key sentinels of infection and tissue damage via activation of self-assembling pattern recognition receptors (inflammasomes), which trigger inflammation and cell death in a caspase-1 dependent process. These studies examine the relationship between A1PI expression in primary monocytes and monocytic cell lines, and inflammatory cytokine expression in response to inflammasome directed stimuli.MethodsIL-1 β expression was examined in lung macrophages expressing wild type A1PI (A1PI-M) or disease-associated Z isoform A1PI (A1PI-Z). Inflammatory cytokine release was evaluated in THP-1 monocytic cells or THP-1 cells lacking the inflammasome adaptor ASC, transfected with expression vectors encoding A1PI-M or A1PI-Z. A1PI-M was localized within monocytes by immunoprecipitation in hypotonic cell fractions. Cell-free titration of A1PI-M was performed against recombinant active caspase-1 in vitro.ResultsIL-1 β expression was elevated in lung macrophages expressing A1PI-Z. Overexpression of A1PI-M in THP-1 monocytes reduced secretion of IL-1β and TNF-α. In contrast, overexpression of A1PI-Z enhanced IL-1β and TNF- α secretion in an ASC dependent manner. A1PI-Z-enhanced cytokine release was inhibited by a small molecule caspase-1 inhibitor but not by high levels of exogenous wtA1PI. Cytosolic localization of A1PI-M in monocytes was not diminished with microtubule-inhibiting agents. A1PI-M co-localized with caspase-1 in gel-filtered cytoplasmic THP-1 preparations, and was co-immunoprecipitated with caspase 1 from nigericin-stimulated THP-1 cell lysate. Plasma-derived A1PI inhibited recombinant caspase-1 mediated conversion of a peptide substrate in a dose dependent manner.ConclusionsOur results suggest that monocyte/macrophage-expressed A1PI-M antagonizes IL-1β secretion possibly via caspase-1 inhibition, a function which disease-associated A1PI-Z may lack. Therapeutic approaches which limit inflammasome responses in patients with A1PI deficiency, in combination with A1PI augmentation, may provide additional respiratory tissue-sparing benefits.
Highlights
Since the first report in 1969 that alpha-1 proteinase inhibitor (A1PI) inhibits elastase [1], it has been widely accepted that excessive elastolytic activity underlies rapidly-progressing emphysema in patients with low plasma A1PI levels
To understand whether macrophage A1PI contributions to lung tissue homeostasis might differ among different disease states, we performed immunohistochemical assessment of A1PI in tissues acquired at autopsy from patients with severe cystic fibrosis (CF) associated respiratory disease, acute fatal lower respiratory infection (LRI), lung disease associated with A1PI deficiency and controls without known lung disease (Fig. 1 and not shown)
Accumulation of A1PI positive cells in the airway lumen was striking in both RSV-associated LRI of infancy and in CF, two diseases in which dampened innate responses of tissue macrophages to pathogens have been invoked in respiratory tissue destruction [14,15,16]
Summary
Since the first report in 1969 that alpha-1 proteinase inhibitor (A1PI) inhibits elastase [1], it has been widely accepted that excessive elastolytic activity underlies rapidly-progressing emphysema in patients with low plasma A1PI levels. Expression of elastase-inhibiting A1PI in lung macrophages and monocytes was initially reported in 1985 [2], the biological significance was not understood. More recent observations in primary monocytes cultured ex vivo linked expression of aggregation prone, disease associated isoforms of A1PI with increased inflammatory cytokine expression, induction of apoptosis and/or autophagy, and endoplasmic reticulum (ER) stressinduced changes termed the unfolded protein response (UPR) [3,4]. How these and other changes in monocyte function may contribute to lung tissue damage in patients with A1PI deficiency has been incompletely explored
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