MicroRNA-146b protects kidney injury during urinary tract infections by modulating macrophage polarization

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ABSTRACT

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) can lead to severe kidney injury. However, the molecular mechanisms underlying the pathological process of kidney injury are still incompletely understood. In the present study, we demonstrate that microRNA-146b (miR-146b) deficiency aggravates kidney injury during UTIs caused by UPEC. In a mouse kidney infection model utilizing urosepsis isolate CFT073, we found that miR-146b expression significantly increased in the early stages of UPEC infection. Also, miR-146b-deficient mice displayed exacerbated inflammation in the kidney injury with severe M1 macrophage infiltration. Additionally, the results showed that miR-146b targeted interferon regulatory factor 5-regulated M1 macrophage polarization during UTIs. The results suggested that miR-146b contributed significantly to the control of kidney damage during UTIs, highlighting that miR-146b might be used as a novel therapeutic target for treating kidney injury during UTIs.

IMPORTANCE

Kidney injury during acute urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) is an important public health problem. However, how kidney injury develops during UPEC infection is still unclear. Although antibiotic therapy is currently an effective treatment for UTI, it cannot avoid kidney injury. MicroRNAs have gained extensive attention as essential molecules capable of regulating the autoimmune response. Among these, microRNA-146b (miR-146b) is involved in regulating inflammatory responses. In the present study, we demonstrated that miR-146b played an essential role in the development of kidney injury during UTIs caused by UPEC. The results showed that miR-146b may suppress M1 macrophage polarization and alleviate acute kidney injury. Furthermore, the miR-146b activator, agomir, in order to upregulate miR-146b, was effective in treating kidney damage by inhibiting the activation of M1 macrophages. In conclusion, our findings elucidated the mechanisms by which miR-146b alleviated kidney injury induced by UTIs, shed new light on the relationship between microRNA and bacterial infection, and provided a novel therapeutic target for treating this common bacterial infection.

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Most cited references 45

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Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

Marco Orecchioni, Yanal Ghosheh, Akula Pramod … (2019)

Macrophages are found in tissues, body cavities, and mucosal surfaces. Most tissue macrophages are seeded in the early embryo before definitive hematopoiesis is established. Others are derived from blood monocytes. The macrophage lineage diversification and plasticity are key aspects of their functionality. Macrophages can also be generated from monocytes in vitro and undergo classical (LPS+IFN-γ) or alternative (IL-4) activation. In vivo, macrophages with different polarization and different activation markers coexist in tissues. Certain mouse strains preferentially promote T-helper-1 (Th1) responses and others Th2 responses. Their macrophages preferentially induce iNOS or arginase and have been called M1 and M2, respectively. In many publications, M1 and classically activated and M2 and alternatively activated are used interchangeably. We tested whether this is justified by comparing the gene lists positively [M1(=LPS+)] or negatively [M2(=LPS–)] correlated with the ratio of IL-12 and arginase 1 in transcriptomes of LPS-treated peritoneal macrophages with in vitro classically (LPS, IFN-γ) vs. alternatively activated (IL-4) bone marrow derived macrophages, both from published datasets. Although there is some overlap between in vivo M1(=LPS+) and in vitro classically activated (LPS+IFN-γ) and in vivo M2(=LPS–) and in vitro alternatively activated macrophages, many more genes are regulated in opposite or unrelated ways. Thus, M1(=LPS+) macrophages are not equivalent to classically activated, and M2(=LPS–) macrophages are not equivalent to alternatively activated macrophages. This fundamental discrepancy explains why most surface markers identified on in vitro generated macrophages do not translate to the in vivo situation. Valid in vivo M1/M2 surface markers remain to be discovered.

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NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.

Konstantin Taganov, Mark Boldin, Kuang-Jung Chang … (2006)

Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-kappaB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3' UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.

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Macrophages: development and tissue specialization.

Chen Varol, Alexander Mildner, Steffen Jung (2015)

Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.

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Author and article information

Contributors

Huabao Xiong:

ORCID: https://orcid.org/0000-0003-0180-2104

Yiping Han: Role: Editor

Indira U. Mysorekar: Role: Invited Editor

Journal

Journal ID (nlm-ta): mBio

Journal ID (iso-abbrev): mBio

Journal ID (publisher-id): mbio

Title: mBio

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2150-7511

Publication date (Electronic, collection): Nov-Dec 2023

Publication date (Electronic, pub): 01 November 2023

Publication date PMC-release: 01 November 2023

Volume: 14

Issue: 6

Electronic Location Identifier: e02094-23

Affiliations

[1 ]Institute of Immunology and Molecular Medicine, Jining Medical University; , Jining, China

[2 ]Jining Key Laboratory of Immunology, Jining Medical University; , Jining, China

[3 ]Cheeloo College of Medicine, Shandong University; , Jinan, China

[4 ]Department of Dermatology and Laboratory of Medical Mycology, Jining No. 1 People’s Hospital; , Jining, Shandong, China

Columbia University; , New York, New York, USA

Baylor College of Medicine; , Houston, Texas, USA

Author notes

Address correspondence to Huabao Xiong, xionghbl@ 123456yahoo.com

The authors declare no conflict of interest.

Author information

Changying Wang https://orcid.org/0000-0002-3024-6664

Dongmei Shi https://orcid.org/0000-0002-0886-4191

Huabao Xiong https://orcid.org/0000-0003-0180-2104

Article

Publisher ID: 02094-23 Publisher ID: mbio.02094-23

DOI: 10.1128/mbio.02094-23

PMC ID: 10870822

PubMed ID: 37909731

SO-VID: cec91fec-6057-43f0-a5b8-4fc5818c25af

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 08 August 2023

Date accepted : 14 September 2023

Page count

supplementary-material: 1, authors: 9, Figures: 8, Tables: 1, References: 46, Pages: 20, Words: 9277

Funding

Funded by: Natural Science Foundation of Shandong Province;

Award ID: NO. ZR2021QH017

Award Recipient : Changying Wang

Funded by: MOST | National Natural Science Foundation of China (NSFC);

Award ID: NO. 82101864

Award Recipient : Changying Wang

Funded by: MOST | National Natural Science Foundation of China (NSFC);

Award ID: NO. 81874169

Award Recipient : Huabao Xiong

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cover-date November/December 2023

ScienceOpen disciplines: Life sciences

Keywords: acute kidney injury,macrophage differentiation,urinary tract infections,uropathogenic escherichia coli

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: acute kidney injury, macrophage differentiation, urinary tract infections, uropathogenic escherichia coli

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MicroRNA-146b protects kidney injury during urinary tract infections by modulating macrophage polarization

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IMPORTANCE

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Karger: Nephrology

Most cited references 45

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.

Macrophages: development and tissue specialization.

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