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Peer-reviewedCC BY 4.0Frontiers in Immunology

Ulvan, carrageenan, and fucoidan: comparative immunomodulatory mechanisms and future directions in major algal sulfated polysaccharides

  • Shuang Zhao1,2
  • Zhangyi Xia3
  • Jinlin Liu4,5
  • Meijing Zhang1,2
  • Maozi Lin1,2
  • Guangmao Ding1,2,6
  • Longchen Tang1,2
  • Fang Su1,2
  • Jingyi Sun7
  • Chao Zhao8
8 affiliations
  1. 1Fujian Provincial Key Laboratory of Coastal Basin Environment, Fujian Polytechnic Normal University
  2. 2Ocean College, Fujian Polytechnic Normal University
  3. 3State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University
  4. 4Key Laboratory of Marine Ecological Monitoring and Restoration Technologies, East China Sea Ecological Center, Ministry of Natural Resources
  5. 5Project Management Office of China National Scientific Seafloor Observatory, Tongji University
  6. 6College of Life Sciences, Fujian Agriculture and Forestry University
  7. 7Hebei Engineering Research Center for Ecological Restoration of Seaward Rivers and Coastal Waters, Hebei University of Environmental Engineering
  8. 8College of Marine Sciences, Fujian Agriculture and Forestry University
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Abstract

Sulfated polysaccharides derived from marine algae have attracted considerable interest in innate immunity research due to their structural diversity and pronounced immunomodulatory activities. Ulvan, carrageenan, and fucoidan, derived from green, red, and brown algae, respectively, represent three paradigmatic classes of algal sulfated polysaccharides. This review establishes a four-tier analytical framework, namely “structural features, receptor recognition, signaling pathways, and immune outcomes”, to systematically compare their mechanistic differences in innate immune modulation. This framework provides, for the first time, a unified causal chain from molecular structure to immune effector phenotypes. Ulvan is characterized by coordinated TLR4/cGAS-STING dual pathways: it drives pro-inflammatory responses via the TLR4-MyD88-NF-κB axis while inducing type I interferon production through the cGAS-STING-TBK1-IRF3 cascade. TBK1, as a shared downstream node of both the TLR4-TRIF and cGAS-STING pathways, may mediate signal integration and amplification, thereby conferring a distinctive advantage to ulvan in antiviral immunity. Carrageenan exhibits dual TLR4/NLRP3 activities, with κ/ι/λ subtypes displaying a functional spectrum from localized pro-inflammation to systemic immunostimulation, determined by their sulfate content and gelation properties. A critical distinction must be made between high-molecular-weight native carrageenan (>100 kDa), which is minimally absorbed in the intestine and considered safe, and low-molecular-weight degraded carrageenan (<50 kDa), which carries inflammatory and toxic risks. Fucoidan achieves immunomodulatory pleiotropy through dual TLR4/CLR recognition and concurrent engagement of multiple signaling cascades, encompassing NF-κB-driven pro-inflammation, bidirectional NLRP3 inflammasome regulation, and complement C3 activation. The antiviral effect of fucoidan via the STING pathway, potentially dependent on ROS-mediated DNA damage or endoplasmic reticulum stress, mechanistically differs from ulvan’s cGAS-STING activation. The structural basis driving this pathway selectivity resides in an inverse gradient relationship between sulfate and uronic acid contents across the three polysaccharides: sulfate content ranks as fucoidan > carrageenan > ulvan, while uronic acid content follows the opposite order. This inverse gradient serves as the first unified structural principle explaining differential receptor preferences and pathway selection among these three distinct classes of algal polysaccharides. Based on this framework, we propose differentiated polysaccharide design strategies tailored to three therapeutic objectives (pro-inflammation, antiviral defense, and immune balance), offering a roadmap for structure-guided immunomodulation using algal sulfated polysaccharides.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026ulvan,
  title = {{Ulvan, carrageenan, and fucoidan: comparative immunomodulatory mechanisms and future directions in major algal sulfated polysaccharides}},
  author = {Shuang Zhao and Zhangyi Xia and Jinlin Liu and Meijing Zhang and Maozi Lin and Guangmao Ding and Longchen Tang and Fang Su and Jingyi Sun and Chao Zhao},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1949951},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949951/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Ulvan, carrageenan, and fucoidan: comparative immunomodulatory mechanisms and future directions in major algal sulfated polysaccharides
AU  - Shuang Zhao
AU  - Zhangyi Xia
AU  - Jinlin Liu
AU  - Meijing Zhang
AU  - Maozi Lin
AU  - Guangmao Ding
AU  - Longchen Tang
AU  - Fang Su
AU  - Jingyi Sun
AU  - Chao Zhao
PY  - 2026
DA  - 2026/10/12
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1949951
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949951/full
AB  - Sulfated polysaccharides derived from marine algae have attracted considerable interest in innate immunity research due to their structural diversity and pronounced immunomodulatory activities. Ulvan, carrageenan, and fucoidan, derived from green, red, and brown algae, respectively, represent three paradigmatic classes of algal sulfated polysaccharides. This review establishes a four-tier analytical framework, namely “structural features, receptor recognition, signaling pathways, and immune outcomes”, to systematically compare their mechanistic differences in innate immune modulation. This framework provides, for the first time, a unified causal chain from molecular structure to immune effector phenotypes. Ulvan is characterized by coordinated TLR4/cGAS-STING dual pathways: it drives pro-inflammatory responses via the TLR4-MyD88-NF-κB axis while inducing type I interferon production through the cGAS-STING-TBK1-IRF3 cascade. TBK1, as a shared downstream node of both the TLR4-TRIF and cGAS-STING pathways, may mediate signal integration and amplification, thereby conferring a distinctive advantage to ulvan in antiviral immunity. Carrageenan exhibits dual TLR4/NLRP3 activities, with κ/ι/λ subtypes displaying a functional spectrum from localized pro-inflammation to systemic immunostimulation, determined by their sulfate content and gelation properties. A critical distinction must be made between high-molecular-weight native carrageenan (>100 kDa), which is minimally absorbed in the intestine and considered safe, and low-molecular-weight degraded carrageenan (<50 kDa), which carries inflammatory and toxic risks. Fucoidan achieves immunomodulatory pleiotropy through dual TLR4/CLR recognition and concurrent engagement of multiple signaling cascades, encompassing NF-κB-driven pro-inflammation, bidirectional NLRP3 inflammasome regulation, and complement C3 activation. The antiviral effect of fucoidan via the STING pathway, potentially dependent on ROS-mediated DNA damage or endoplasmic reticulum stress, mechanistically differs from ulvan’s cGAS-STING activation. The structural basis driving this pathway selectivity resides in an inverse gradient relationship between sulfate and uronic acid contents across the three polysaccharides: sulfate content ranks as fucoidan > carrageenan > ulvan, while uronic acid content follows the opposite order. This inverse gradient serves as the first unified structural principle explaining differential receptor preferences and pathway selection among these three distinct classes of algal polysaccharides. Based on this framework, we propose differentiated polysaccharide design strategies tailored to three therapeutic objectives (pro-inflammation, antiviral defense, and immune balance), offering a roadmap for structure-guided immunomodulation using algal sulfated polysaccharides.
SN  - 1664-3224
ER  -