Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Abstract

Neutrophils (polymorphonuclear neutrophils [PMNs]) play an elaborate role in the innate immune response against invading pathogens. Recent research provided evidence that PMNs can play a modulatory role in inflammation next to their primary role of phagocytosis. In the current study, we investigated whether neutrophils can modulate the innate immune response against Candida albicans. Production of the proinflammatory cytokines IL-1β and TNF-α by human PBMCs in response to C. albicans or LPS was decreased by coculture of PMNs; however, the anti-inflammatory cytokine IL-10 remained unaffected. Using Transwells and cells of patients with chronic granulomatous disease, we show that this downregulation of proinflammatory cytokine production was independent of phagocytosis and reactive oxygen species but was dependent on a soluble factor. We suggest that neutrophil-derived proteases are responsible for the downregulation of IL-1β and TNF-α, as cytokine production could be recovered by addition of α1-antitrypsin, an endogenous inhibitor of serine proteases. PMN lysates and neutrophil elastase could degrade recombinant human IL-1β and TNF-α but not IL-10, and this could be inhibited by addition of α1-antitrypsin. Moreover, we also provide evidence that the dampening effect of PMNs is present in vivo in a murine zymosan-induced arthritis model and a murine experimental endotoxemia model. Altogether, our data show that PMNs can dampen the proinflammatory response to C. albicans by protease-mediated degradation of cytokines. This observation suggest that PMNs might play a important regulatory role in the host defense against C. albicans and can be important for understanding the regulation of inflammation in general.

Neutrophil Extracellular Traps Downregulate Lipopolysaccharide-Induced Activation of Monocyte-Derived Dendritic Cells

“…Indeed, antimicrobial molecules such as LL-37, lactoferrin, and a-defensins can inhibit DC activation (33,54,56,57). In addition, elastase can induce TGF-b (32) and reduce proinflammatory cytokine production by moDC, thus promoting CD4 + lymphocyte T regulatory polarization (31). Recently, Schauer et al (45) evidenced that aggregated NETs promote the resolution of inflammation in a murine model of gout, via in particular elastase-induced cytokine and chemokine degradation; as we did not evidence such a proteolytic effect of purified NETs on TNF-a in our study, we can assume that other mechanisms are involved.…”

“…Activated PMN can promote DC migration (28) and also modulate DC maturation and activation through cell-cell contacts (29), ectosome release (30), or mediator secretion. Interestingly, several granule-derived mediators such as lactoferrin, LL-37, calprotectins, a-defensins, elastase, bactericidal/permeability-increasing protein, MPO, and proteinase 3 have been shown to either downregulate (31)(32)(33)(34)(35)(36)(37) or upregulate (33,(38)(39)(40)(41)) DC functions, depending on the study.…”

17β-Estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs

“…Functionally, in vitro exposure of neutrophils to E2 (i) increases degranulation, elastase release, and production of reactive oxygen species, (ii) inhibits caspase 3/9 and delays apoptosis, and (iii) increases cell adhesion molecules and interactions with endothelial cells (54)(55)(56). Neutrophils produce and release cytokines and chemokines (e.g., CXCL1 and CXCL8), present antigen, and express surface receptors necessary for recruitment and activation of monocytes, DCs, and T cells, illustrating a central role for neutrophils in regulating innate and adaptive immune responses (57)(58)(59). Data from the present study demonstrate that in vivo treatment with E2 increases pulmonary concentrations of neutrophil chemoattractants, including CCL3 and CXCL1, and recruitment of neutrophils to the lungs during IAV infection.…”

The mercurial nature of neutrophils: still an enigma in ARDS?

“…For example, MMP-9 increases the activity of IL-8 (CXCL8) through amino terminal processing but degrades CXCL1 (Gro-␣) (175). The activation of chemokines enhances neutrophil migration, which may augment lung injury (160,165), whereas the inactivation of proinflammatory cytokines and chemokines may be beneficial for the resolution of ongoing neutrophilia and lung inflammation (64,119). MMP-9 endopeptidase activity also results in the generation of the extracellular matrix breakdown product of collagen, N-acetyl Pro-GlyPro (Ac-PGP), which is highly chemotactic for neutrophils and has been associated with inflammatory lung disease (57,179).…”