Adipose-Derived Mesenchymal Stem Cells Ameliorating Pseudomonas aeruginosa–induced Acute Lung Infection via Inhibition of NLRC4 Inflammasome

Abstract

BackgroundPseudomonas aeruginosa (PA) is one of the most common Gram-negative bacteria causing hospital-acquired pulmonary infection, with high drug resistance and mortality. Therefore, it is urgent to introduce new non-antibiotic treatment strategies. Mesenchymal stem cells (MSCs), as important members of the stem cell family, were demonstrated to alleviate pathological damage in acute lung injury. However, the potential mechanism how MSC alleviate acute lung infection caused by PA remains unclear.ObjectiveThe purpose of this study was to investigate the effects of Adipose-derived mesenchymal stem cells (ASCs) on acute pulmonary infections and the possible mechanisms how ASCs reduce pulmonary inflammation induced by PA.MethodsThe therapeutic and mechanistic effects of ASCs on PA pulmonary infection were evaluated respectively in a murine model as well as in an in vitro model stimulated by PA and co-cultured with ASCs.Results1. ASCs treatment significantly reduced the bacterial load, inflammation of lung tissue and histopathological damage by PA. 2. PA infection mainly activated Nod-like receptor containing a caspase activating and recruitment domain 4 (NLRC4) inflammasome in the lung of mice. ASCs attenuated acute lung infection in mice by inhibiting NLRC4 inflammasome activation. 3. NLRC4−/− mice showed a significant improvement in survival rate and lung bacterial load after PA infection. 4. ASCs mainly increased expression and secretion of STC‐1 in response to PA‐stimulated NLRC4 inflammasome activation.ConclusionsPA infection attenuated macrophage phagocytosis through activation of NLRC4 inflammasome in macrophages, which eventually led to pulmonary inflammatory damage in mouse; ASCs reduced the activation of NLRC4 inflammasome in macrophages induced by PA infection, thereby increasing the phagocytic ability of macrophages, and ultimately improving lung tissue damage in mouse; ASCs may inhibit NLRC4 inflammasome through the secretion of STC-1.

A unique NLRC4 receptor from echinoderms mediates Vibrio phagocytosis via rearrangement of the cytoskeleton and polymerization of F-actin

“…This question is worthy of our in-depth study. Another most relevant finding is that Aj-NLRC4 is involved in phagocytosis ( Fig 10 ), while other (vertebrate) NLRC4 proteins are active in inflammasome activation and could even act antiphagocytically as part of inflammation [ 92 ]. We speculate that this completely different method of recruitment and the pathway by which pathogen invasion is resisted could occur because AjNLRC4 lacks the traditional LRR and CARD domains, making it unable to perform the corresponding functions of traditional NLRs.…”

Pyroptosis and respiratory diseases: A review of current knowledge

“…It was revealed that anthrax lethal toxin could induce NLRP1-dependent pyroptosis in mouse macrophages, which promoted lung inflammation and resultant exacerbation of ALI (149). Recently, Li et al found that the activation of NLRC4 inflammasome in macrophages triggered by pseudomonas aeruginosa infection led to pulmonary inflammatory damage, while Adipose-Derived Mesenchymal Stem Cells improved lung tissue damage in mice through reducing the NLRC4 inflammasome activation in macrophages (150). Wang et al found that HMGB1 could participate in LPS−induced of ALI by activating the AIM2 inflammasome in macrophages (151).…”

Microfluidic Tools for Enhanced Characterization of Therapeutic Stem Cells and Prediction of Their Potential Antimicrobial Secretome

“…The indirect antimicrobial effects of MSCs, partly mediated via Toll-like receptor (TLR) signaling [110], proved to (I) modulate proinflammatory cytokine and chemokine induction; (II) to release immunosuppressive factors that inhibit excessive proliferation and infiltration of inflammatory T cells and Natural Killer (NK) cells; and (III) to increase phagocytic activity of monocytes and neutrophils [111]. In addition to the inhibition of the NLRP3 inflammasome [112] by BM-MSCs [113], the ASCs [113] also reduced the activation of NLRC4 inflammasome [114,115], thereby increasing the phagocytic ability of macrophages induced by P. aeruginosa infection [116]. Treatment with MSCs diminished the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kb) in lung injury induced by sepsis [117].…”