Teleost Bone Morphogenetic Protein 2 (BMP2): Dynamic responses to infection and negative feedback regulation of inflammatory cytokines in gills of flounder (Paralichthys olivaceus)

Zefan Xu; Yingqin Liu; Xiuzhen Sheng; Xiaoqian Tang; Jing Xing; Heng Chi; Wenbin Zhan

doi:10.1016/j.fsi.2026.111329

Teleost Bone Morphogenetic Protein 2 (BMP2): Dynamic responses to infection and negative feedback regulation of inflammatory cytokines in gills of flounder (Paralichthys olivaceus)

Fish Shellfish Immunol. 2026 Apr 7:111329. doi: 10.1016/j.fsi.2026.111329. Online ahead of print.

Authors

Zefan Xu¹, Yingqin Liu¹, Xiuzhen Sheng², Xiaoqian Tang³, Jing Xing³, Heng Chi³, Wenbin Zhan³

Affiliations

¹ Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, P. R. China.
² Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, P. R. China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China. Electronic address: xzsheng@ouc.edu.cn.
³ Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, P. R. China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China.

PMID: 41956331
DOI: 10.1016/j.fsi.2026.111329

Abstract

The gill mucosal barrier is pivotal for teleost defense, yet the immunoregulatory mechanisms within it remain to be fully elucidated. Bone Morphogenetic Protein 2 (BMP2) plays multifunctional roles in mammalian immunity but is poorly understood in teleosts. This study investigated the role of BMP2 in the mucosal immunity of flounder (Paralichthys olivaceus), focusing on the gill mucosae. The characteristics of flounder BMP2 were firstly analyzed and its specific antibody was generated. BMP2 was constitutively highly expressed in immune tissues (e.g., gills, spleen, liver, and gut), especially in gills, and localized to gill epithelial and a portion of WGA⁺ (Wheat Germ Agglutinin) goblet cells. Edwardsiella tarda infection induced inflammatory responses and myeloperoxidase (MPO)⁺ neutrophil aggregates in gills. Intraperitoneal injection of E. tarda triggered a sustained BMP2 signaling pathway and inflammatory response, whereas immersion infection induced a transient surge. In both models, BMP2 pathway activation was characterized by the upregulation of bmp2, alk3, and the inhibitory smad6, alongside the suppression of the target id1. Crucially, pharmacological blockade of BMP signaling with LDN-193189 amplified the expression of pro-inflammatory cytokines (il-1β, il-6, tnf-α, nlrp3) and disrupted mucosal mucin secretion, indicating a loss of homeostatic control. These findings provided the first systematic evidence that BMP2 functioned as a critical negative feedback regulator in gill mucosal immunity in teleosts. By constraining excessive inflammatory responses and supporting mucus barrier integrity, BMP2 appeared to play a pivotal role in maintaining mucosal homeostasis against bacterial pathogens, revealing an evolutionarily conserved immunoregulatory dimension of the BMP pathway with implications for fish aquaculture health management.

Keywords: Bone Morphogenetic Protein 2 (BMP2); Flounder (Paralichthys olivaceus); Gill-associated lymphoid tissue; Inflammation; Negative feedback regulation.