title: IL-1α and IL-1β-producing macrophages populate lung tumor lesions in mice.
abstract: Macrophages highly populate tumour microenvironment and are referred to as tumor-associated macrophages (TAMs). The inflammasome is a multiprotein complex responsible of IL-1 like cytokines release, which biology has been widely studied by using bone-marrow-derived macrophages to mimic a physiological and/or host defense condition. To understand the role of this complex in lung tumor-associated macrophages (TAMs), we isolated and cultured broncho-alveolar lavage (BAL)-derived cells of lung tumor-bearing mice. The stimulation of lung TAMs with LPS+ATP increased the release of IL-1β. The inhibition of NLRP3 by means of glybenclamide significantly reduced IL-1β release. Similarly, C3H-derived, caspase-1 ko and caspase-11 ko TAMs released significantly reduced levels of IL-1β. Moreover, the stimulation of lung TAMs with the sole LPS induced a significant release of IL-1α, which was significantly reduced after caspase-1 pharmacological inhibition, and in TAMs genetically lacking caspase-1 and caspase-11. The inhibition of calpain I/II by means of MDL28170 did not alter IL-1α release after LPS treatment of lung TAMs. To note, the inoculation of LPS-treated bone marrow-derived macrophages into carcinogen-exposed mice increased lung tumor formation. In contrast, the depletion of TAMs by means of clodronate liposomes reduced lung tumorigenesis, associated to lower in vivo release of IL-1α and IL-1β.In conclusion, our data imply lung tumor lesions are populated by macrophages which pro-tumor activity is regulated by the activation of the NLRP3 inflammasome that leads to the release of IL-1α and IL-1β in a caspase-11/caspase-1-dependent manner.
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Fisciano, 84084, Italy.|PhD Program in Drug Discovery and Development, University of Salerno, Salerno, Fisciano, 84084, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Terlizzi
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Fisciano, 84084, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Colarusso
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Fisciano, 84084, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Popolo
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Fisciano, 84084, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Fisciano, 84084, Italy.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sorrentino
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002154:Calpain / Q000037:antagonists & inhibitors; D063646:Carcinogenesis / Q000473:pathology*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053471:Caspases, Initiator; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D004151:Dipeptides; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004002:Clodronic Acid; D008770:Methylnitrosourea; D000255:Adenosine Triphosphate; D002154:Calpain; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1; D005905:Glyburide; C058076:calpain inhibitor III
keywords: IL-1α; IL-1β; NLRP3 inflammasome; lung cancer; tumor-associated macrophages