title: Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus.
abstract: Nonclassical monocytes undergo intravascular patrolling in blood vessels, positioning them ideally to coordinate responses to inflammatory stimuli. Under some circumstances, the actions of monocytes have been shown to involve promotion of neutrophil recruitment. However, the mechanisms whereby patrolling monocytes control the actions of neutrophils in the circulation are unclear. Here, we examined the contributions of monocytes to antibody- and neutrophil-dependent inflammation in a model of in situ immune complex-mediated glomerulonephritis. Multiphoton and spinning disk confocal intravital microscopy revealed that monocytes patrol both uninflamed and inflamed glomeruli using β2 and α4 integrins and CX3CR1. Monocyte depletion reduced glomerular injury, demonstrating that these cells promote inappropriate inflammation in this setting. Monocyte depletion also resulted in reductions in neutrophil recruitment and dwell time in glomerular capillaries and in reactive oxygen species (ROS) generation by neutrophils, suggesting a role for cross-talk between monocytes and neutrophils in induction of glomerulonephritis. Consistent with this hypothesis, patrolling monocytes and neutrophils underwent prolonged interactions in glomerular capillaries, with the duration of these interactions increasing during inflammation. Moreover, neutrophils that interacted with monocytes showed increased retention and a greater propensity for ROS generation in the glomerulus. Also, renal patrolling monocytes, but not neutrophils, produced TNF during inflammation, and TNF inhibition reduced neutrophil dwell time and ROS production, as well as renal injury. These findings show that monocytes and neutrophils undergo interactions within the glomerular microvasculature. Moreover, evidence indicates that, in response to an inflammatory stimulus, these interactions allow monocytes to promote neutrophil recruitment and activation within the glomerular microvasculature, leading to neutrophil-dependent tissue injury.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia;
authors.forename: Michaela
authors.initials: M
authors.lastname: Finsterbusch
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia;
authors.forename: Pam
authors.initials: P
authors.lastname: Hall
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia;
authors.forename: Anqi
authors.initials: A
authors.lastname: Li
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia;
authors.forename: Sapna
authors.initials: S
authors.lastname: Devi
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia;
authors.forename: Clare L V
authors.initials: CL
authors.lastname: Westhorpe
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia; Department of Nephrology, Monash Medical Centre, Clayton, VIC 3168, Australia; Department of Paediatric Nephrology, Monash Medical Centre, Clayton, VIC 3168, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia; michael.hickey@monash.edu.
authors.forename: Michael J
authors.identifier: 0000-0003-2354-357X
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002196:Capillaries / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D016023:Integrins / Q000276:immunology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology*; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; D016023:Integrins; D017382:Reactive Oxygen Species
keywords: glomerulonephritis; inflammation; monocyte–neutrophil interaction; reactive oxygen species; tumor necrosis factor