Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus

Villanueva, Eneida C.; Yalavarthi, Srilakshmi; Berthier, Céline C.; Hodgin, Jeffrey B.; Khandpur, Ritika; Lin, Andrew M.; Rubin, Cory J.; Zhao, Wenpu; Olsen, Stephen H.; Klinker, Matthew W.; Shealy, David J.; Denny, Michael F.; Plumas, Joël; Chaperot, Laurence; Kretzler, Matthias; Bruce, Allen T.; Kaplan, Mariana J.

doi:10.4049/jimmunol.1100450

Cited by 1,068 publications

(1,273 citation statements)

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“…However, if dysregulated, it can also cause significant tissue injury. Inappropriate recruitment and activation of neutrophils are recognized as major contributors to organ damage in numerous inflammatory diseases, including inflammatory arthritis, acute respiratory distress syndrome, systemic lupus erythematosus, and acute glomerulonephritis (1)(2)(3)(4). Although our understanding of the molecular basis of neutrophil recruitment is well-developed, less is known about the interactions of neutrophils with other circulating immune cells during the development of the innate inflammatory response.…”

mentioning

confidence: 99%

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

Finsterbusch

Hall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

141

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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 neutrophildependent inflammation in a model of in situ immune complexmediated glomerulonephritis. Multiphoton and spinning disk confocal intravital microscopy revealed that monocytes patrol both uninflamed and inflamed glomeruli using β 2 and α 4 integrins and CX 3 CR1. 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.monocyte-neutrophil interaction | inflammation | glomerulonephritis | reactive oxygen species | tumor necrosis factor N eutrophil recruitment is a crucial event in the response to tissue injury and host defense against pathogens. However, if dysregulated, it can also cause significant tissue injury. Inappropriate recruitment and activation of neutrophils are recognized as major contributors to organ damage in numerous inflammatory diseases, including inflammatory arthritis, acute respiratory distress syndrome, systemic lupus erythematosus, and acute glomerulonephritis (1-4). Although our understanding of the molecular basis of neutrophil recruitment is well-developed, less is known about the interactions of neutrophils with other circulating immune cells during the development of the innate inflammatory response. However, over the last decade, evidence has emerged that neutrophil recruitment and function during inflammation can be influenced by another circulating immune cell-the monocyte (5-10).Monocytes exist in two major populations,...

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mentioning

confidence: 99%

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

Finsterbusch

Hall

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

141

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“…The newly discovered form of neutrophil cell death, NETosis, in which neutrophils throw out chromatin fibers (neutrophil extracellular traps; NETs) containing antibacterial peptidesand nuclear antigens, have been implicated in the SLE pathogenesis [121]. Increased NETosis [122] of SLE patients, as well as reduced capacity to degrade NETs have been demonstrated in vitro [123,124]. It has also been suggested that dysfunctional neutrophils can contribute to organ damage [121].…”

Section: Supar and Neutrophilsmentioning

confidence: 99%

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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“…De nombreuses études ont démontré l'existence d'une dérégulation des NET au cours du lupus, associant une augmentation de leur production et une altération de leur dégradation [15,16,37]. L'augmentation de production des NET est déclenchée par la présence de concentrations élevées de cytokines pro-inflammatoires (IL-18, IFN [interféron ]).…”

Section: Lupus éRythémateux Systémiqueunclassified

La pêche miraculeuse des filets du neutrophile

2014

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Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus

Cited by 1,068 publications

References 64 publications

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

La pêche miraculeuse des filets du neutrophile

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