title: Monosodium Urate Crystals Induce Upregulation of NK1.1-Dependent Killing by Macrophages and Support Tumor-Resident NK1.1+ Monocyte/Macrophage Populations in Antitumor Therapy.
abstract: Macrophages display phenotypic and functional heterogeneity dependent on the changing inflammatory microenvironment. Under some conditions, macrophages can acquire effector functions commonly associated with NK cells. In the current study, we investigated how the endogenous danger signal monosodium urate (MSU) crystals can alter macrophage functions. We report that naive, primary peritoneal macrophages rapidly upregulate the expression of the NK cell-surface marker NK1.1 in response to MSU crystals but not in response to LPS or other urate crystals. NK1.1 upregulation by macrophages was associated with mechanisms including phagocytosis of crystals, NLRP3 inflammasome activation, and autocrine proinflammatory cytokine signaling. Further analysis demonstrated that MSU crystal-activated macrophages exhibited NK cell-like cytotoxic activity against target cells in a perforin/granzyme B-dependent manner. Furthermore, analysis of tumor hemopoietic cell populations showed that effective, MSU-mediated antitumor activity required coadministration with Mycobacterium smegmatis to induce IL-1β production and significant accumulation of monocytes and macrophages (but not granulocytes or dendritic cells) expressing elevated levels of NK1.1. Our findings provide evidence that MSU crystal-activated macrophages have the potential to develop tumoricidal NK cell-like functions that may be exploited to boost antitumor activity in vivo.
authors.affiliation: Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
authors.forename: Stefanie
authors.identifier: http://orcid.org/0000-0002-5990-494X
authors.initials: S
authors.lastname: Steiger
authors.affiliation: Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuhn
authors.affiliation: Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
authors.affiliation: Malaghan Institute of Medical Research, Wellington 6242, New Zealand jharper@malaghan.org.nz.
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis*; D002352:Carrier Proteins / Q000276:immunology; D045744:Cell Line, Tumor; D053804:Granzymes / Q000378:metabolism; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D020102:Mycobacterium smegmatis / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000096:biosynthesis*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D054353:Perforin / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D015854:Up-Regulation; D014527:Uric Acid / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000950:Antigens, Ly; D002352:Carrier Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; C527211:Klrb1c protein, mouse; D008070:Lipopolysaccharides; D055651:NK Cell Lectin-Like Receptor Subfamily B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D054353:Perforin; D014527:Uric Acid; D053804:Granzymes; C509214:Gzmb protein, mouse