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产生白细胞介素-22的固有淋巴细胞的治疗性激活可增强宿主对艰难梭菌感染的防御能力。

Therapeutic activation of IL-22-producing innate lymphoid cells enhances host defenses to Clostridioides difficile infection.

作者信息

Mears Kevin S, Denny Joshua E, Maslanka Jeffrey R, Mdluli Nontokozo V, Hulit Ellie N, Matsuda Rina, Furth Emma E, Buffie Charlie G, Abt Michael C

机构信息

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

出版信息

Cell Rep. 2025 Apr 22;44(4):115438. doi: 10.1016/j.celrep.2025.115438. Epub 2025 Mar 25.

DOI:10.1016/j.celrep.2025.115438
PMID:40138315
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12115236/
Abstract

Clostridioides difficile causes debilitating colitis via secreted toxins that disrupt the intestinal barrier, and toxemia is associated with severe disease. Thus, therapies that fortify the intestinal barrier will reduce the severity of infection. Innate lymphoid cells (ILCs) are critical in the defense against acute C. difficile infection and represent a promising therapeutic target to limit disease. Here, we report that oral administration of the Toll-like receptor (TLR) 7 agonist R848 limits intestinal damage and protects mice from lethal C. difficile infection without impacting pathogen burden or altering the intestinal microbiome. R848 induced interleukin (IL)-22 secretion by ILCs, leading to STAT3 phosphorylation in the intestinal epithelium and increased stem cell proliferation. Genetic ablation of ILCs, IL-22, or epithelial-specific STAT3 abrogated R848-mediated protection. R848 reduced intestinal permeability following infection and limited systemic toxin dissemination. Combined, these data identify an immunostimulatory molecule that activates IL-22 production in ILCs to enhance host tissue defenses following C. difficile infection.

摘要

艰难梭菌通过分泌破坏肠道屏障的毒素引发使人虚弱的结肠炎，毒血症与严重疾病相关。因此，增强肠道屏障的疗法将减轻感染的严重程度。固有淋巴细胞（ILC）在抵御急性艰难梭菌感染中起关键作用，是限制疾病的一个有前景的治疗靶点。在此，我们报告口服Toll样受体（TLR）7激动剂R848可限制肠道损伤，并保护小鼠免受致命性艰难梭菌感染，而不影响病原体载量或改变肠道微生物群。R848诱导ILC分泌白细胞介素（IL）-22，导致肠道上皮细胞中的信号转导和转录激活因子3（STAT3）磷酸化，并增加干细胞增殖。ILC、IL-22或上皮特异性STAT3的基因敲除消除了R848介导的保护作用。R848降低了感染后肠道的通透性，并限制了全身毒素的扩散。综合来看，这些数据确定了一种免疫刺激分子，该分子可激活ILC中IL-22的产生，以增强艰难梭菌感染后宿主组织的防御能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/23a4ad25ee2c/nihms-2076696-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/57954f2c4db4/nihms-2076696-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/2276b6c0a5f4/nihms-2076696-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/bc1b6ab48813/nihms-2076696-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/634d821be1f8/nihms-2076696-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/affc70b3e26f/nihms-2076696-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/23a4ad25ee2c/nihms-2076696-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/57954f2c4db4/nihms-2076696-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/2276b6c0a5f4/nihms-2076696-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/bc1b6ab48813/nihms-2076696-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/634d821be1f8/nihms-2076696-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/affc70b3e26f/nihms-2076696-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/12115236/23a4ad25ee2c/nihms-2076696-f0006.jpg

相似文献

[1]
Therapeutic activation of IL-22-producing innate lymphoid cells enhances host defenses to Clostridioides difficile infection.

Cell Rep. 2025-4-22

[2]
Loss of Interleukin-10 (IL-10) Signaling Promotes IL-22-Dependent Host Defenses against Acute Clostridioides difficile Infection.

Infect Immun. 2021-4-16

[3]
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[4]
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[5]
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[6]
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Cell Host Microbe. 2025-2-12

[7]
Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice.

Immunology. 2015-4

[8]
Aging impairs protective host defenses against Clostridioides (Clostridium) difficile infection in mice by suppressing neutrophil and IL-22 mediated immunity.

Anaerobe. 2018-12

[9]
Citrulline Inhibits Clostridioides difficile Infection With Anti-inflammatory Effects.

Cell Mol Gastroenterol Hepatol. 2025

[10]
Innate Immune Defenses Mediated by Two ILC Subsets Are Critical for Protection against Acute Clostridium difficile Infection.

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引用本文的文献

[1]
Innate Lymphoid Cells in Inflammatory Bowel Disease.

Cells. 2025-6-2

本文引用的文献

[1]
NKp46 ILC3s promote early neutrophil defense against infection through GM-CSF secretion.

Proc Natl Acad Sci U S A. 2024-11-5

[2]
Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.

Proc Natl Acad Sci U S A. 2024-5-7

[3]
IL-22-dependent responses and their role during infection.

Infect Immun. 2024-5-7

[4]
Hyperbaric oxygen augments susceptibility to infection by impairing gut microbiota ability to stimulate the HIF-1α-IL-22 axis in ILC3.

Gut Microbes. 2024

[5]
The role of Th17 cells in inflammatory bowel disease and the research progress.

Front Immunol. 2022

[6]
Bezlotoxumab prevents extraintestinal organ damage induced by infection.

Gut Microbes. 2022

[7]
Oral delivery of IL-22 mRNA-loaded lipid nanoparticles targeting the injured intestinal mucosa: A novel therapeutic solution to treat ulcerative colitis.

Biomaterials. 2022-9

[8]
The TLR7/8 agonist R848 optimizes host and tumor immunity to improve therapeutic efficacy in murine lung cancer.

Int J Oncol. 2022-7

[9]
Intestinal Inflammation and Altered Gut Microbiota Associated with Inflammatory Bowel Disease Render Mice Susceptible to Clostridioides difficile Colonization and Infection.

mBio. 2021-6-29

[10]
Reprogramming Intestinal Epithelial Cell Polarity by Interleukin-22.

Front Med (Lausanne). 2021-4-12

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