TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

Cells. 2022 Aug 28;11(17):2674. doi: 10.3390/cells11172674.

Abstract

TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

Keywords: Akt/STAT; MAPK/NF-κB; TcpC; UPEC; macrophage polarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Escherichia coli Infections* / metabolism
  • Escherichia coli Proteins* / metabolism
  • Humans
  • Interleukin-4 / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages* / metabolism
  • Macrophages* / microbiology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT6 Transcription Factor / metabolism
  • Urinary Tract Infections* / metabolism
  • Urinary Tract Infections* / microbiology
  • Uropathogenic Escherichia coli* / genetics
  • Uropathogenic Escherichia coli* / metabolism
  • Virulence Factors* / metabolism

Substances

  • Escherichia coli Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stat6 protein, mouse
  • TcpC protein, E coli
  • Virulence Factors
  • Interleukin-4
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (81671613 to J.P.), the Natural Science Foundation of Zhejiang Province (LQ20H100001 to J.F.), the Science and Technology Bureau of Hangzhou, Zhejiang Province (20212013B05 to J.P.) and the Scientific Research Foundation of Zhejiang University City College (J-202102 to J.F., J-202103 to S.L.). The funders had no role in study’s design, data collection and analysis, decision to publish, or preparation of the manuscript.