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

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.

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“…Two main signaling pathways, the Akt/mTORC/LXR pathway and the JAK/STAT6 pathway, are two major signaling pathway for M2 polarization. (Bi et al, 2019;Fang et al, 2022). Besides, Th2 cell-secreted molecules, such as IL-4, can also induce the differentiation of macrophages toward M2 phenotype, thereby alleviating inflammation by inhibiting the mitogen-activated protein kinase signaling pathway (Zhao et al, 2016).…”

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis

“…Subsequent trans-regulation and cis-regulation analyses were carried out to further understand the signaling pathways and molecular networks involved in the differentially expressed LncRNAs of MWCNTs- and PBS-treated THP-1 Mφ cells. From the top 20 KEGG pathways (Figures S8A,B and S9A,B) and molecular networks (Figures S8C and S9C) in trans-regulation and cis-regulation, we found M2-related signaling pathways including the TNF pathway, NF-κB pathway, TGF-β pathway, and MAPK pathway were significantly highlighted. − …”

Dendrocandin U fromDendrobium officinaleKimura et Migo Inhibits M1 Polarization in Alveolar Macrophage by Suppressing NF‐κB Signaling Pathway

“…TNF‐α plays an indispensable role in regulating immune cells and inflammatory responses, and TNF‐α dysregulation can cause inflammatory responses such as fever, edema and tissue damage [45] . In addition, CD86 is often used as a membrane molecular marker of macrophage M1 subtype [46] . In this study, we firstly investigated the effect of dendrocandin U on the production of iNOS, TNF‐α and CD86, and it was found that dendrocandin U could inhibit the expression or secretion of iNOS, TNF‐α and CD86 at 20 μM (Figure 5A, B, C).…”

“…[45] In addition, CD86 is often used as a membrane molecular marker of macrophage M1 subtype. [46] In this study, we firstly investigated the effect of dendrocandin U on the production of iNOS, TNF-α and CD86, and it was found that dendrocandin U could inhibit the expression or secretion of iNOS, TNF-α and CD86 at 20 μM (Figure 5A, B, C). These results suggest that dendrocandin U plays an anti-inflammatory role by inhibiting the polarization of MHÀ S towards M1.…”