MicroRNA-223 Dampens Pulmonary Inflammation during Pneumococcal Pneumonia

Cells. 2023 Mar 21;12(6):959. doi: 10.3390/cells12060959.

Abstract

Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia.

Keywords: Streptococcus pneumoniae; inflammation; microRNA-223; neutrophils; pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Inflammation / genetics
  • Inflammation / microbiology
  • Inflammation / pathology
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • MicroRNAs* / genetics
  • Pneumonia, Pneumococcal* / genetics
  • Pneumonia, Pneumococcal* / microbiology
  • Pneumonia, Pneumococcal* / pathology
  • Streptococcus pneumoniae

Substances

  • MicroRNAs
  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse

Grants and funding

This research was funded by a German Federal Ministry of Education and Research (BMBF) grant to M.W., grant number e:Med CAPSyS (01ZX1304B, 01ZX1604B) and an academic stipend awarded to C.G. by the Interdisciplinary Center of Infection Biology and Immunity (ZIBI). G.N., S.-M.W. and M.W. were supported by the BMBF and by the Agence Nationale de la Recherche (ANR) in the framework of MAPVAP (01KI2124). A.D.G. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation); project ID 114933180–SFB-TR84, sub-project Z01b. N.S. received funding from the DFG (project ID 114933180–SFB-TR84, sub-projects B01, C09 and Z02) and BMBF (e:Med CAPSyS grants 01ZX1304B and 01ZX1604B). M.W. received funding from the DFG (project ID 114933180–SFB-TR84, sub-projects C06 and C09; and project ID 431232613–SFB-1449, sub-project B02), the BMBF in the framework of e:Med CAPSyS (01ZX1304B, 01ZX1604B), PROVID (01KI20160A), e:Med SYMPATH (01ZX1906A), NUM-NAPKON (01KX2021, 01KX2121) and the BIH (CM-COVID). H.K. and M.S. received funding from the BMBF in the framework of e:Med CAPSyS (01ZX1304A), PROVID (01KI20160C) and e:Med SYMPATH (01ZX1906B). C.G. and P.P. are supported by the Charité 3R.