Roles of neutrophils in the regulation of the extent of human inflammation through delivery of IL-1 and clearance of chemokines

Abstract

This study examined the establishment of neutrophilic inflammation in humans. We tested the hypotheses that neutrophil recruitment was associated with local CXCL8 production and that neutrophils themselves might contribute to the regulation of the size of the inflammatory response. Humans were challenged i.d. with endotoxin. Biopsies of these sites were examined for cytokine production and leukocyte recruitment by qPCR and IHC. Additional in vitro models of inflammation examined the ability of neutrophils to produce and sequester cytokines relevant to neutrophilic inflammation. i.d. challenge with 15 ng of a TLR4-selective endotoxin caused a local inflammatory response, in which 1% of the total biopsy area stained positive for neutrophils at 6 h, correlating with 100-fold up-regulation in local CXCL8 mRNA generation. Neutrophils themselves were the major source of the early cytokine IL-1β. In vitro, neutrophils mediated CXCL8 but not IL-1β clearance (>90% clearance of ≤2 nM CXCL8 over 24 h). CXCL8 clearance was at least partially receptor-dependent and modified by inflammatory context, preserved in models of viral infection but reduced in models of bacterial infection. In conclusion, in a human inflammatory model, neutrophils are rapidly recruited and may regulate the size and outcome of the inflammatory response through the uptake and release of cytokines and chemokines in patterns dependent on the underlying inflammatory stimulus.

Regulation of Neutrophil Apoptosis Differs after in vivo Transmigration to Skin Chambers and Synovial Fluid: A Role for Inflammasome-Dependent Interleukin-1β Release

“…The skin chamber neutrophils spontaneously produced and released this particular cytokine also during in vitro culture. Although we cannot rule out that some of the IL-1β originate from other cells, human neutrophils have been shown to produce substantial amounts of IL-1β [17], and upon transmigration to skin, both the gene [4] and protein [27] are significantly upregulated specifically in these cells. The IL-1β release was partly suppressed by inhibition of caspase 1, which implies that transmigration to skin chambers induces continuous inflammasome activation.…”

Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis

“…Neutrophils subsequently increase the activation of transcription factors that produce inflammatory chemokines. Thus begins a vicious cycle of inflammation and airway destruction . Inflammatory chemokine production is also stimulated by pulmonary microbial infections which occur in the vast majority of patients with CF.…”

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

“…Eliminating inter-species translational barriers and accurately mimicking the clinical phenotype qualitatively if not quantitatively, it affords real-time interpretation of inflammatory influences, consequences and an opportunity to test interventions. Endotoxin may also be administered endobronchially 20 , intradermally 21 or in combination with IV LPS 22 to explore local inflammatory responses in different compartments. Less widely employed alternative methodologies include infusion of proximal pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin (IL) 6 19 .…”