Abstract
BackgroundOur previous study shows that Adipose tissue‐derived mesenchymal stem cells (ASCs) are a promising strategy for cell‐based therapy against pulmonary infection with Pseudomonas aeruginosa (P. aeruginosa), but the underlying mechanisms remain unclear.MethodscDNA microarray assay was performed to explore the transcriptome of ASCs primed by P. aeruginosa. Small interfering RNA (siRNA) was constructed to select the receptor candidates for P. aeruginosa recognition and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) production in ASCs. The soluble protein chimeras containing the extracellular domain of human CD69 fused to the Fc region of human immunoglobulin IgG1 were used as a probe to validate the recognition of P. aeruginosa. The association between CD69 and extracellular regulated protein kinases 1/2 (ERK1/2) was explored via co‐immunoprecipitation, siRNA, and inhibitor. The murine models of P. aeruginosa pneumonia treated with WT‐ASCs, GM‐CSF −/−‐ASCs Cd69 −/−‐ASCs or Erk1 −/−‐ASCs were used to determine the role of GM‐CSF, CD69, and ERK1 in ASCs against P. aeruginosa infection.ResultsWe showed that C‐type lectin receptor CD69 mediated the protective effects of ASCs partly through GM‐CSF. CD69 could specifically recognize P. aeruginosa and regulate GM‐CSF secretion of ASCs. CD69 regulated the production of GM‐CSF via ERK1 in ASCs after P. aeruginosa infection. Moreover, the Administration of ASCs with deficiency of CD69 or ERK1 completely blocked its protective effects in a murine model of P. aeruginosa pneumonia.ConclusionsCD69 recognizes P. aeruginosa and further facilitates ERK1 activation, which plays a crucial role in ASCs‐based therapy against P. aeruginosa pneumonia. CD69 may be a novel target molecule to improve ASCs‐based therapy against P. aeruginosa infection.
Highlights
Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium, causes life-threatening pneumonia in immunocompromised and hospitalized patients
The Administration of Adipose tissue-derived mesenchymal stem cells (ASCs) with deficiency of CD69 or ERK1 completely blocked its protective effects in a murine model of P. aeruginosa pneumonia
Heat map analysis showed that granulocytemacrophage colony-stimulating factor (GM-CSF) was the most significantly upregulated (Figure 1A) after P. aeruginosa stimulation, with about 60 folds increment, which was verified by Quantitative realtime polymerase chain reaction (PCR) (Figure 1B)
Summary
Pseudomonas aeruginosa, a ubiquitous Gram-negative bacterium, causes life-threatening pneumonia in immunocompromised and hospitalized patients. The development of alternative therapeutic strategies for P. aeruginosa pneumonia is urgently needed.[1,2]. Adipose tissue-derived mesenchymal stem cells (ASCs), with the advantages of higher cell concentration and less invasive capability, have more advantages in clinical application than bone-marrow-derived mesenchymal stem/stromal cells as well as mesenchymal stem/stromal cells from other origins.[3] ASCs have been used to protect the host against colitis and sepsis.[4] our previous study revealed that ASCs exhibited protective effects against P. aeruginosa pulmonary infection through inhibiting the production of host prostaglandin E2, which subsequently improved phagocytosis and the bactericidal properties of macrophages.[5] the underlying mechanisms for the interaction of ASCs with P. aeruginosa remain unclear
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