Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination

Hui Liu; Lirong Xu; Enhao Lu; Chenchen Tang; Hanxiao Zhang; Yanwu Xu; Yuanyuan Yu; Naomi Ong; Xiao-Dong Yang; Qilong Chen; Yuejuan Zheng

doi:10.1093/jleuko/qiae075

Platycodin D facilitates antiviral immunity through inhibiting cytokine storm via targeting K63-linked TRAF6 ubiquitination

J Leukoc Biol. 2024 Mar 22:qiae075. doi: 10.1093/jleuko/qiae075. Online ahead of print.

Authors

Hui Liu^{1

2}, Lirong Xu^{1

2}, Enhao Lu³, Chenchen Tang^{1

2}, Hanxiao Zhang^{1

2}, Yanwu Xu^{1

2}, Yuanyuan Yu^{1

2}, Naomi Ong^{1

2}, Xiao-Dong Yang^{1

2}, Qilong Chen^{2

4}, Yuejuan Zheng^{1

2}

Affiliations

¹ The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
³ The Third Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
⁴ Central Laboratory, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China.

PMID: 38518381
DOI: 10.1093/jleuko/qiae075

Abstract

Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases. As one of the major terpenoid saponins extracted from Platycodon grandiflorum, Platycodin D (PD) has been reported to play several roles, including anti-inflammation, analgesia, anti-cancer, hepatoprotection, and immunoregulation. However, the therapeutic roles of PD to treat influenza virus infection remains unknown. Here, we show that PD can protect the body weight loss in severely infected influenza mice, alleviate lung damage, and thus improve the survival rate. More specifically, PD protects flu mice via decreasing the immune cell infiltration into lungs and downregulating the overactivated inflammatory response. Western blot and immunofluorescence assays exhibited that PD could inhibit the activation of TAK1/IKK/NF-κB and MAPK pathways. Besides that, CETSA, SPR and immunoprecipitation assays indicated that PD binds with TRAF6 to decrease its K63 ubiquitination after R837 stimulation. Additionally, siRNA interference experiments exhibited that PD could inhibit the secretion of IL-1β and TNF-α in TRAF6-dependent manner. Altogether, our results suggested that PD is a promising drug candidate for treating influenza. Our study also offered a scientific explanation for the commonly used Platycodon grandiflorum in many anti-epidemic classic formulas. Due to its host-directed regulatory role, PD may serve as an adjuvant therapeutic drug in conjunction with other antiviral drugs to treat the flu.

Keywords: Platycodin D (PD); TRAF6; anti-inflammatory; influenza virus; lung damage; macrophage; ubiquitination.

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