Interleukin-33 Increases Antibacterial Defense by Activation of Inducible Nitric Oxide Synthase in Skin

Abstract

Interleukin-33 (IL-33) is associated with multiple diseases, including asthma, rheumatoid arthritis, tissue injuries and infections. Although IL-33 has been indicated to be involved in Staphylococcus aureus (S. aureus) wound infection, little is known about how IL-33 is regulated as a mechanism to increase host defense against skin bacterial infections. To explore the underlying intricate mechanism we first evaluated the expression of IL-33 in skin from S. aureus-infected human patients. Compared to normal controls, IL-33 was abundantly increased in skin of S. aureus-infected patients. We next developed a S. aureus cutaneous infection mouse model and found that IL-33 was significantly increased in dermal macrophages of infected mouse skin. The expression of IL-33 by macrophages was induced by staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) via activation of toll-like receptor 2(TLR2) –mitogen-activated protein kinase (MAPK)-AKT-signal transducer and activator of transcription 3(STAT3) signaling pathway as PGN and LTA failed to induce IL-33 in Tlr2-deficient peritoneal macrophages, and MAPK,AKT, STAT3 inhibitors significantly decreased PGN- or LTA-induced IL-33. IL-33, in turn, acted on macrophages to induce microbicidal nitric oxygen (NO) release. This induction was dependent on inducible nitric oxide synthase (iNOS) activation, as treatment of macrophages with an inhibitor of iNOS, aminoguanidine, significantly decreased IL-33-induced NO release. Moreover, aminoguanidine significantly blocked the capacity of IL-33 to inhibit the growth of S. aureus, and IL-33 silencing in macrophages significantly increased the survival of S. aureus in macrophages. Furthermore, the administration of IL-33-neutralizing antibody into mouse skin decreased iNOS production but increased the survival of S. aureus in skin. These findings reveal that IL-33 can promote antimicrobial capacity of dermal macrophages, thus enhancing antimicrobial defense against skin bacterial infections.

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

“…Furthermore, concerning the small number of infliximab-treated cases or female patients, this study revealed notable observations regarding correlations among pro-inflammatory genes, anti-TNF-α treatment type and gender. It was observed that etanercept and infliximab exhibited similar effects on the expression of the three innate immune response factors, IL-33, TLR-2 and -9, in psoriatic skin lesions; however, the present data indicate that TLR-2 and IL-33 may share a common stimulation pattern in psoriatic plaques, in line with a previous report on inflamed skin (39). Male patients may exhibit a distinct biological response to etanercept compared to females, implying a different pathophysiological mechanism of psoriatic plaques.…”

Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases

“…In this model, IL-33 improved the antimicrobial capacity of dermal macrophages with increased nitric oxide (NO) production via inducible NO synthase (iNOS). The inhibition of iNOS with aminoguanidine significantly blocked the capacity of IL-33 to inhibit the growth of S. aureus, whereas IL-33 silencing in macrophages significantly increased survival of S. aureus in macrophages (51). In another study, recombinant IL-33 administration on S. aureus-infected skin promoted the proliferation of neutrophils and CXCR2 expression and consequent neutrophil influx into infectious sites for wound healing (52).…”

“…In the skin, IL-33 is abundantly expressed in Staphylococcus aureus-infected patients compared to healthy subjects. In a mouse model of S. aureus skin infection, staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) activated the TLR2 signaling pathway, leading to IL-33 overexpression in dermal macrophages (51). In this model, IL-33 improved the antimicrobial capacity of dermal macrophages with increased nitric oxide (NO) production via inducible NO synthase (iNOS).…”

The IL-33/ST2 axis: Role in health and disease

“…IL-33 is expressed in healthy skin, predominantly as the fulllength precursor [89,90], and skin cells exposed to inflammatory cytokines, infectious agents such as Staphylococcus aureus, or UVB radiation, produce high levels of IL-33 mRNA [89,91]. In a S. aureus infection model in mouse skin, high levels of IL-33 were produced by macrophages that subsequently induced an antimicrobial state through nitric oxide generation [89].…”

“…In a S. aureus infection model in mouse skin, high levels of IL-33 were produced by macrophages that subsequently induced an antimicrobial state through nitric oxide generation [89]. On the other hand, in human skin explants exposed to UVB radiation there was induction of IL-33 expression by keratinocytes and fibroblasts, suggesting that IL-33-producing fibroblasts may promote an innate immune response by recruitment of neutrophils and mast cells [91].…”