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Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1α in an AIM2 inflammasome-dependent manner.
Am J Pathol 2015; 185(11):3115-24AJ

Abstract

Plasmacytoid dendritic cells (pDCs) highly populate lung tumor masses and are strictly correlated to bad prognosis, yet their role in lung cancer is controversial. To understand their role in lung cancer, we isolated pDCs from human samples of lung obtained from non-small cell lung cancer patients undergoing thoracic surgery. Tumor masses presented a higher percentage of pDCs than healthy tissues; pDCs were in the immunosuppressive phenotype, as determined by higher levels of CD33 and PD-L1. Despite higher HLA-A and HLA-D expression, cancerous pDCs did not exert cytotoxic activity against tumor cells but instead promoted their proliferation. In this scenario, cancerous pDCs were able to produce high levels of IL-1α. This effect was observed on the specific activation of the inflammasome absent in melanoma 2 (AIM2), which led to higher cytoplasmic calcium release responsible for calpain activation underlying IL-1α release. The blockade of type I interferon receptor and of AIM2 via the addition of LL-37 significantly reduced the release of IL-1α, which was still high after Nod-like receptor P3 inhibition via glibenclamide. More important, mitochondrial-derived reactive oxygen species sequester diminished AIM2-dependent IL-1α release. Our data demonstrate that lung tumor-associated pDCs are responsive to the activation of AIM2 that promotes calcium efflux and reactive oxygen species from mitochondria, leading to calpain activation and high levels of IL-1α, which facilitate tumor cell proliferation in the lung.

Authors+Show Affiliations

Department of Pharmacy, University of Salerno, Fisciano, Italy. Electronic address: rsorrentino@unisa.it.Department of Pharmacy, University of Salerno, Fisciano, Italy.Department of Medicine and Surgery, University of Salerno, Fisciano, Italy.Department of Pharmacy, University of Salerno, Fisciano, Italy.Department of Pharmacy, University of Salerno, Fisciano, Italy.Division of the Respiratory System, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.Division of Pneumological and Bronchial Endoscopy, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.Department of Pharmacy, University of Salerno, Fisciano, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26506473

Citation

Sorrentino, Rosalinda, et al. "Human Lung Cancer-derived Immunosuppressive Plasmacytoid Dendritic Cells Release IL-1α in an AIM2 Inflammasome-dependent Manner." The American Journal of Pathology, vol. 185, no. 11, 2015, pp. 3115-24.
Sorrentino R, Terlizzi M, Di Crescenzo VG, et al. Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1α in an AIM2 inflammasome-dependent manner. Am J Pathol. 2015;185(11):3115-24.
Sorrentino, R., Terlizzi, M., Di Crescenzo, V. G., Popolo, A., Pecoraro, M., Perillo, G., ... Pinto, A. (2015). Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1α in an AIM2 inflammasome-dependent manner. The American Journal of Pathology, 185(11), pp. 3115-24. doi:10.1016/j.ajpath.2015.07.009.
Sorrentino R, et al. Human Lung Cancer-derived Immunosuppressive Plasmacytoid Dendritic Cells Release IL-1α in an AIM2 Inflammasome-dependent Manner. Am J Pathol. 2015;185(11):3115-24. PubMed PMID: 26506473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1α in an AIM2 inflammasome-dependent manner. AU - Sorrentino,Rosalinda, AU - Terlizzi,Michela, AU - Di Crescenzo,Vincenzo G, AU - Popolo,Ada, AU - Pecoraro,Michela, AU - Perillo,Giuseppe, AU - Galderisi,Antonio, AU - Pinto,Aldo, PY - 2015/01/07/received PY - 2015/07/06/revised PY - 2015/07/09/accepted PY - 2015/10/28/entrez PY - 2015/10/28/pubmed PY - 2016/6/3/medline SP - 3115 EP - 24 JF - The American journal of pathology JO - Am. J. Pathol. VL - 185 IS - 11 N2 - Plasmacytoid dendritic cells (pDCs) highly populate lung tumor masses and are strictly correlated to bad prognosis, yet their role in lung cancer is controversial. To understand their role in lung cancer, we isolated pDCs from human samples of lung obtained from non-small cell lung cancer patients undergoing thoracic surgery. Tumor masses presented a higher percentage of pDCs than healthy tissues; pDCs were in the immunosuppressive phenotype, as determined by higher levels of CD33 and PD-L1. Despite higher HLA-A and HLA-D expression, cancerous pDCs did not exert cytotoxic activity against tumor cells but instead promoted their proliferation. In this scenario, cancerous pDCs were able to produce high levels of IL-1α. This effect was observed on the specific activation of the inflammasome absent in melanoma 2 (AIM2), which led to higher cytoplasmic calcium release responsible for calpain activation underlying IL-1α release. The blockade of type I interferon receptor and of AIM2 via the addition of LL-37 significantly reduced the release of IL-1α, which was still high after Nod-like receptor P3 inhibition via glibenclamide. More important, mitochondrial-derived reactive oxygen species sequester diminished AIM2-dependent IL-1α release. Our data demonstrate that lung tumor-associated pDCs are responsive to the activation of AIM2 that promotes calcium efflux and reactive oxygen species from mitochondria, leading to calpain activation and high levels of IL-1α, which facilitate tumor cell proliferation in the lung. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/26506473/Human_lung_cancer_derived_immunosuppressive_plasmacytoid_dendritic_cells_release_IL_1α_in_an_AIM2_inflammasome_dependent_manner_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(15)00437-X DB - PRIME DP - Unbound Medicine ER -