Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy.
Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy.
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DOI：
10.1038/s41467-022-33331-8
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发表时间：
2022-10-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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白细胞介素-22 （IL-22）在肠屏障稳态中的作用仍有争议。在这里，我们绘制了IL-22在人类结肠上皮类器官中调控的转录景观，并评估了IL-22介导的途径在溃疡性结肠炎（UC）中的生物学、功能和临床意义。我们发现IL-22调节的促炎途径参与微生物识别、癌症和免疫细胞趋化；最显著的是涉及CXCR2+中性粒细胞。il- 22介导的cxc家族中性粒细胞活性趋化因子表达的转录调控在物种间高度保守，依赖于STAT3信号，在CXCR2+中性粒细胞募集到结肠组织中具有功能和病理上的重要作用。在UC患者中，结肠活检中IL-22调节转录物的富集程度与结肠中性粒细胞浸润相关，并且在对ustekinumab治疗无反应的患者中富集。我们的数据进一步揭示了IL-22在人类疾病中的生物学作用，并强调了其在调节致病性免疫途径（包括中性粒细胞趋化性）中的功能。IL-22调节的转录网络在UC中具有功能和临床重要性，影响患者轨迹和对生物干预的反应性。ustekinumab（一种靶向IL-23的生物药物）无应答的机制目前尚不清楚。在这里，作者表明，IL-22（一种对IL-23敏感的细胞因子）调控的转录程序在对ustekinumab无反应的溃疡性结肠炎患者中富集，并与结肠中性粒细胞募集增加和上游IL-22调节因子的激活相关。
The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention. Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
2.5
作者：
Kulaylat, Mahmoud N.;Dayton, Merril T.
通讯作者：
Dayton, Merril T.
影响因子：
30.5
作者：
Duhen, Thomas;Geiger, Rebekka;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
24.5
作者：
Geboes, K;Riddell, R;Löfberg, R
通讯作者：
Löfberg, R