IL-20 Signaling in Activated Human Neutrophils Inhibits Neutrophil Migration and Function

Abstract

Neutrophils possess multiple antimicrobial mechanisms that are critical for protection of the host against infection with extracellular microbes, such as the bacterial pathogen Staphylococcus aureus. Recruitment and activation of neutrophils at sites of infection is driven by cytokine and chemokine signals that directly target neutrophils via specific cell surface receptors. The IL-20 subfamily of cytokines has been reported to act at epithelial sites and contribute to psoriasis, wound healing, and anti-inflammatory effects during S. aureus infection. However, the ability of these cytokines to directly affect neutrophil function remains incompletely understood. Here, we show that human neutrophils altered their expression of IL-20 receptor chains upon migration and activation in vivo and in vitro. Such activation of neutrophils under conditions mimicking infection with S. aureus conferred responsiveness to IL-20 that manifested as modification of actin polymerization and inhibition of a broad range of actin-dependent functions, including phagocytosis, granule exocytosis, and migration. Consistent with the previously described homeostatic and anti-inflammatory properties of IL-20 on epithelial cells, the current studies provide evidence that IL-20 directly targets and inhibits key inflammatory functions of neutrophils during infection with S. aureus.

Role of negative regulation of immune signaling pathways in neutrophil function

“…Using an in vitro model of PMN migration, Gough et al . recently demonstrated that IL-20 actively inhibits PMN transmigration across bronchoepithelial cells in an ERK1/2 dependent fashion [53]. A similar IL-20 mediated inhibition of PMN trafficking has been reported in vivo in a mouse model of corneal healing [54].…”

“…Recently Gough et al found that IL-20 inhibits PMN phagocytosis, degranulation and migration by modifying actin polymerization in an S. aureus model of infection [53]. IL-20 signals through two different receptor complexes made up of heterodimers of the common IL-20RB subunit and either IL-20RA (complex type I) or IL-22RA (type II).…”

“…While PMN from peripheral blood of healthy donors expressed only IL-22RA, exposure to S. aureus resulted in increased expression of IL-20RB in IL-8 or TNFα primed PMN in vivo and in vitro . Following S. aureus infection, treatment with IL-20 reduced intracellular bacterial killing in primed PMN, by impairing phagocytosis [53]. IL-20 induced phosphorylation of ERK1/2 but not p38 MAPK, and inhibition of ERK1/2 signaling restored the phagocytic ability of TNFα primed PMN suggesting that IL-20 inhibits PMN phagocytosis in an ERK1/2 dependent fashion.…”

“…Specifically, exocytosis of tertiary (gelatinase) granules in response to S. aureus was inhibited by IL-20 in TNFα-primed PMN [53]. Tertiary granules are more highly associated with actin than primary and secondary granule populations.…”

IL-20-Receptor Signaling Delimits IL-17 Production in Psoriatic Inflammation

“…Transgenic mice overexpressing IL-20 or IL-24 display some epidermal hyperplasia, although those overexpressing IL-19 do not (He and Liang, 2010). Interestingly, all three cytokines have been associated with both pro-and anti-inflammatory functions, depending on their context and/or study (Autieri, 2018;Cantó et al, 2014;Caparró s and Frances, 2018;Fujimoto et al, 2017;Gough et al, 2017;Horiuchi et al, 2015;Kako et al, 2016;Kragstrup, 2016;Kumar et al, 2018;Matsuo et al, 2015;Myles et al, 2013;Niess et al, 2018;Steinert et al, 2017;Xie et al, 2016). The in vivo roles of IL-19, IL-20, and IL-24 in psoriatic inflammation warrant further investigation.…”