Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury
Michelangelo Bauwelz Gonzatti,
Beatriz Marton Freire,
Maísa Mota Antunes,
Gustavo Batista de Menezes,
Jhimmy Talbot,
Jean Pierre Schatzmann Peron,
Alexandre Salgado Basso,
Alexandre Castro Keller
Affiliations
Michelangelo Bauwelz Gonzatti
Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4th floor, São Paulo 04023-062, Brazil
Beatriz Marton Freire
Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4th floor, São Paulo 04023-062, Brazil
Maísa Mota Antunes
Department of Morphology, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, Minas Gerais 31270-910, Brazil
Gustavo Batista de Menezes
Department of Morphology, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, Minas Gerais 31270-910, Brazil
Jhimmy Talbot
Fred Hutchinson Cancer Center, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA
Jean Pierre Schatzmann Peron
Department of Immunology-ICB IV, University of São Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo 05508-900, Brazil
Alexandre Salgado Basso
Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4th floor, São Paulo 04023-062, Brazil; Corresponding author
Alexandre Castro Keller
Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4th floor, São Paulo 04023-062, Brazil; Corresponding author
Summary: Invariant Natural Killer T (iNKT) cell activation by α-galactosylceramide (αGC) potentiates cytotoxic immune responses against tumors. However, αGC-induced liver injury is a limiting factor for iNKT-based immunotherapy. Although adrenergic receptor stimulation is an important immunosuppressive signal that curbs tissue damage induced by inflammation, its effect on the antitumor activity of invariant Natural Killer T (iNKT) cells remains unclear. We use mouse models and pharmacological tools to show that the stimulation of the sympathetic nervous system (SNS) inhibits αGC-induced liver injury without impairing iNKT cells’ antitumoral functions. Mechanistically, SNS stimulation prevents the collateral effect of TNF-α production by iNKT cells and neutrophil accumulation in hepatic parenchyma. Our results suggest that the modulation of the adrenergic signaling can be a complementary approach to αGC-based immunotherapy to mitigate iNKT-induced liver injury without compromising its antitumoral activity.
