YWHAZ acts as a regulatory node in Streptococcus pneumoniae-induced pulmonary inflammation.

Authors

Shifei Yao, Yongwen Li, Longze Zhang, Weiwei Zhang, Jiali Chen, Chengmin Deng, Kaifeng Wu

Published in

International immunopharmacology. Volume 186. Pages 117068. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ, 14-3-3ζ), a key regulator of intracellular signaling and inflammatory responses, has not been investigated in Streptococcus pneumoniae (S.pn) infection.
We first employed Western blotting to detect the expression and activation of YWHAZ in murine RAW264.7 macrophages and a mouse model of S.pn pneumonia. A small-molecule inhibitor BV02 was used to pharmacologically block YWHAZ function both in vitro and in vivo. Subsequent evaluations included the production of inflammatory cytokines via ELISA, the detection of autophagy-related biomarkers, bacterial clearance capacity by colony-forming units (CFU) enumeration, and lung pathological injury using HE staining. Furthermore, Western blot was applied to determine the activation of TLR4 and its downstream core signaling pathways, to further elucidate the underlying molecular mechanisms.
S.pn infection induced YWHAZ phosphorylation, which further mediated the activation of the NF-κB and p38MAPK inflammatory signaling pathways. Pharmacological inhibition of YWHAZ with BV02 downregulated NLRP3 and IL-1β expression, and reduced the secretion of key pro-inflammatory cytokines including TNF-α, IL-6, IL-1β, and IL-18. Moreover, BV02 modulated autophagic activity upon S.pn infection and enhanced host bacterial clearance ability. Mechanistically, YWHAZ functions as a pivotal molecular bridge linking TLR4 to downstream pro-inflammatory signaling cascades during host response against S.pn infection.
During S.pn infection, YWHAZ undergoes phosphorylation and functions as a downstream effector of TLR4 signaling. It exacerbates macrophage-mediated inflammatory responses, impairs autophagy-associated bacterial clearance, and aggravates pulmonary immunopathology, highlighting YWHAZ as a promising therapeutic target for pneumococcal pneumonia.

PMID:
42398172
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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