Work

IL-5 and IL-5Ra act as checkpoint inhibitors in regulating neutrophil-mediated cytotoxicity after lung surgery 2609

Year: 2025

Type: article

Abstract: Description We have recently described that eosinophils play a major role in lethal inflammatory immune responses following lung resection. Biologics targeting the cytokine IL-5 as well as IL-5R are FDA approved. We thus used murine homologues to either mediate ADCC of IL-5R expressing cells or neutralize the cytokine IL-5. To our surprise, IL-5 neutralization worsened survival. We noted that IL-5R was expressed not only on eosinophils but also on neutrophils. After IL-5 neutralization and lung resection, neutrophils increased and demonstrated augmented cytotoxicity as measured by CD69, CD107a, and IL-1β. Concomitant depletion of neutrophils improved survival after lung resection and IL-5 neutralization. Evaluation of various proinflammatory cytokines after lung resection demonstrated an increase in GM-CSF, CXCL2, IL-6, and G-CSF. Only G-CSF depletion uniquely reduced IL-5R neutrophil levels, suppressed their activation, and improved survival. These data suggest that IL-5 and IL-5R may act as critical regulators of neutrophil-mediated cytotoxicity when stimulated by G-CSF and possibly other factors. This study suggests that targeting IL-5R and its downstream signaling pathways could offer novel therapeutic approaches for modulating immune responses in postoperative lung injury as well as other processes. Funding Sources NIH grant P01 AI116501. NIH grants R01 AI145108-01 and R01 HL166402. VA grant I01 BX002299-05. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.509