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Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis.

ABSTRACT: Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas.

SUBMITTER: Wright K

PROVIDER: S-EPMC8055004 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis.

Wright Kathryn K de Silva Kumudika K Plain Karren M KM Purdie Auriol C AC Blair Tamika A TA Duggin Iain G IG Britton Warwick J WJ Oehlers Stefan H SH

PLoS pathogens 20210407 4

Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregul ...[more]

PMID: 33826679

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Project description:The liver is the most common site of metastasis for colorectal cancer (CRC). Metastasis suppressor 1 (MTSS1), a potential tumor suppressor gene associated with tumor metastasis, has been reported to play an important role in cancer development. The present study aimed to investigate the effects and underlying mechanisms of MTSS1 on the biological behavior of CRC cells both in vitro and in vivo. A CRC mouse model with a high liver metastatic potential was established by injecting mice with SW1116 cells, and the association between MTSS1 expression levels and the metastatic potential of forming liver metastasis lesions was subsequently analyzed. MTSS1 gain‑ and loss‑of‑function experiments were performed by transfecting the CRC cell lines, SW1116 and DLD‑1, with Plvx‑IRES‑ZsGreen1‑MTSS1 plasmid and short hairpin RNA, respectively. Cell proliferation, migration, invasion and cell cycle distribution were analyzed by MTT, Transwell and flow cytometric assays, respectively. To further determine the underlying mechanisms of MTSS1 in CRC, the expression levels of cell surface chemokine C‑X‑C receptor 4 (CXCR4) and its downstream signaling factors, Rac and cell division cycle 42 (CDC42), were analyzed with or without C‑X‑C motif chemokine ligand 12 (CXCL12) stimulation. The results revealed that as the CRC metastatic potential increased, the expression levels of MTSS1 decreased. The overexpression of MTSS1 exerted an inhibitory effect on cell proliferation, migration and invasion, while the knockdown of MTSS1 exerted the opposite effects in vitro. Flow cytometric analysis and western blot analysis demonstrated that MTSS1 negatively regulated the expression levels of cell surface CXCR4 and its downstream signaling pathway activation. On the whole, the results of the present study indicate that MTSS1 may play an important negative role in CRC metastasis and the underlying mechanisms may involve the downregulation of the CXCR4/CXCL12 signaling axis.

Dataset Information

Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis.

Publications

Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis.

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