The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation

Nechama, Morris; Kwon, Jeahoo; Wei, Shuo; Kyi, A T; Welner, Robert S.; Ben‐Dov, Iddo Z.; Arredouani, Mohamed S.; Asara, John M.; Chen, Chun-Hau; Tsai, Cheng‐Yu; Nelson, Kyle F.; Kobayashi, Koichi S.; Israel, Elliot; Zhou, Xiao Zhen; Nicholson, Linda; Lu, Kun Ping

doi:10.1038/s41467-018-03886-6

Cited by 65 publications

(68 citation statements)

References 73 publications

(84 reference statements)

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“…S3), was detectable promptly after compression and was accompanied by a marked induction of epithelial alarmins, including IL-33 and TSLP. While a supportive activity of these factors has been documented for a variety of accessory immune cells 43,44 , IL-33 and TSLP are central for example to the initiation and enhancement of type 2 response typically seen in asthmatic inflammation [45][46][47][48] . Following compression (3 hr), an increased release of these factors from airway epithelial cells could activate type 2 innate lymphoid cells (ILC2) and augment type 2 inflammation in the lung 43,48,49 .…”

Section: Discussionmentioning

confidence: 99%

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Kılıç

Ameli

Park

et al. 2020

Sci Rep

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Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature. Bronchial epithelial cells (BECs) form a physical barrier that protects pulmonary airways from inhaled irritants and invading pathogens 1,2. Moreover, environmental stimuli such as allergens, pollutants and viruses can induce constriction of the airways 3 and thereby expose the bronchial epithelium to compressive mechanical stress. In BECs, this compressive stress induces structural, biophysical, as well as molecular changes 4,5 , that interact with nearby mesenchyme 6 to cause epithelial layer unjamming 1 , shedding of soluble factors, production of matrix proteins, and activation matrix modifying enzymes, which then act to coordinate inflammatory and remodeling processes 4,7-10. Growing evidence supports the notion that mechanical stress in the airway induces not only developmental, homeostatic and reparative responses in the healthy lung but also pathophysiologic processes in the asthmatic lung 2,11-13. For example, mechanical stimuli induce early inflammatory and remodeling factors 6,7,14,15 , microRNAs (miRs) 16,17 , and cell proliferation 18. Using protein-protein interaction networks, here we compare responses to compressive stress in human BECs (HBECs) obtained from non-asthmatic versus asthmatic donors. Our hypothesis was, that using a systems biology approach to examine the effect of mechanical forces acting on structural cells in the airway, will elucidate the complex transcriptional programs that contribute to disease development and pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Kılıç

Ameli

Park

et al. 2020

Sci Rep

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“…ATRA binds and induces degradation of Pin1 and its substrate PML‐RARA and thereby exerts anticancer activity against APL in cell and animal models and human patients . This anticancer activity of ATRA has been confirmed and expanded to breast cancer, liver cancer even using a different ATRA controlled release formulation, and acute myeloid leukemia (AML), as well as in lupus and asthma . However, the role of Pin1 in mediating ATRA anticancer activity against gastric cancer is not known.…”

Section: Discussionmentioning

confidence: 99%

“…ATRA‐induced Pin1 ablation also exerts antitumor activity against breast cancer by blocking multiple oncogenic pathways . The ability of ATRA to inhibit Pin1 function has been independently confirmed in breast cancer and also expanded to liver cancer, even using a different ATRA controlled release formulation, as well as to lupus and asthma . Although a small study of 182 cases has shown Pin1 overexpression in human gastric cancer, the role of Pin1 in the development and treatment of gastric cancer is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β‐catenin oncogenic pathways

Zhang

Zheng

et al. 2019

Molecular Carcinogenesis

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Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is prolinedirected phosphorylation, which is further regulated by the unique proline isomerase Pin1.Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/β-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.

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“…However, the eventual presence of co-morbidities can induce changes in cancer genetics, molecular, and clinical outcomes, complicating both epidemiologic and mechanistic studies. In fact, several genes and related products involved in highly prevalent illnesses strongly concur to cancer heterogeneity, i.e., hypertension [ 14 , 15 , 16 ], diabetes [ 17 ], allergies [ 18 , 19 , 20 , 21 ] and inflammatory chronic diseases [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Ottaiano

Caraglia

Mauro

et al. 2020

Cancers

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Genetic dynamics underlying cancer progression are largely unknown and several genes involved in highly prevalent illnesses (e.g., hypertension, obesity, and diabetes) strongly concur to cancer phenotype heterogeneity. To study genotype-phenotype relationships contributing to the mutational evolution of colorectal cancer (CRC) with a focus on liver metastases, we performed genome profiling on tumor tissues of CRC patients with liver metastatic disease and no co-morbidities. We studied 523 cancer-related genes and tumor-immune microenvironment characteristics in primary and matched metastatic tissues. We observed a loss of KRAS and SMAD4 alterations and a high granzyme-B+ T-cell infiltration when the disease did not progress. Conversely, gain in KRAS, PIK3CA and SMAD4 alterations and scarce granzyme-B+ T-cells infiltration were observed when the tumor evolved towards a poly-metastatic spread. These findings provide novel insights into the identification of tumor oligo-metastatic status, indicating that some genes are on a boundary line between these two clinical settings (oligo- vs. poly-metastatic CRC). We speculate that the identification of these genes and modification of their evolution could be a new approach for anti-cancer therapeutic strategies.

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The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation

Cited by 65 publications

References 73 publications

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β‐catenin oncogenic pathways

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

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