Dataset Information

Osteoblast Hypoxia-Inducible Factor-1? Pathway Activation Restrains Osteoclastogenesis via the Interleukin-33-MicroRNA-34a-Notch1 Pathway.

ABSTRACT: Functional cross-talk between osteoblasts and osteoclasts is a key process for bone homeostasis. Although osteoblast hypoxia-inducible factor-1? (HIF-1?) pathway activation results in impaired osteoclastogenesis via the direct regulation of osteoprotegerin (OPG), it is unclear whether there are other efficient mediators are involved in osteoblast HIF-1? pathway activation-restrained osteoclast formation. In addition to upregulated OPG, we observed that osteoblast HIF-1? activation led to increased interleukin-33 (IL-33) expression, which was found to inhibit osteoclastogenesis. Mechanistically, HIF-1? facilitates IL-33 expression by binding to -1,504/-1,500?bp on the Il-33 promoter. IL-33, thereby, acts on bone marrow-derived monocytes (BMMs) to reduce their osteoclastic differentiation. Moreover, microRNA-34a-5p (miR-34a-5p)-inhibited Notch1 activation was observed to play a central role in this process. Thereby, the identification of IL-33-miR-34a-5p-Notch1 pathway in the inhibitory effect of osteoblast HIF-1? pathway on osteoclastogenesis uncovers a new mechanism for understanding the effects of HIF-1? on bone remodeling.

SUBMITTER: Kang H

PROVIDER: S-EPMC5650688 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Osteoblast Hypoxia-Inducible Factor-1α Pathway Activation Restrains Osteoclastogenesis <i>via</i> the Interleukin-33-MicroRNA-34a-Notch1 Pathway.

Kang Hui H Yang Kai K Xiao Lianbo L Guo Lei L Guo Changjun C Yan Yufei Y Qi Jin J Wang Fei F Ryffel Bernhard B Li Changwei C Deng Lianfu L

Frontiers in immunology 20171016

Functional cross-talk between osteoblasts and osteoclasts is a key process for bone homeostasis. Although osteoblast hypoxia-inducible factor-1α (HIF-1α) pathway activation results in impaired osteoclastogenesis <i>via</i> the direct regulation of osteoprotegerin (OPG), it is unclear whether there are other efficient mediators are involved in osteoblast HIF-1α pathway activation-restrained osteoclast formation. In addition to upregulated OPG, we observed that osteoblast HIF-1α activation led to ...[more]

PMID: 29085370

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Project description: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.

Dataset Information

Osteoblast Hypoxia-Inducible Factor-1? Pathway Activation Restrains Osteoclastogenesis via the Interleukin-33-MicroRNA-34a-Notch1 Pathway.

Publications

Osteoblast Hypoxia-Inducible Factor-1α Pathway Activation Restrains Osteoclastogenesis <i>via</i> the Interleukin-33-MicroRNA-34a-Notch1 Pathway.

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