Galectin-9 upregulated by Endotoxin causes Depression, Alzheimer's memory loss, Jab Brain Fog and accelerates Cancer
Surging science explodes like a Supernova, so I continue to look at root causes of devastating diseases. Galectin-9 is trending just now and Endotoxin is at the centre.
My good friend Moriarty introduced me to Galectins1 that play important roles in numerous biological processes and he recently wrote about Galection-9.2
Experiments in Mice show the importance of Galectin-9 in Brain Damage.
Moriarty pointed to a key paper on Endotoxin upregulation of Galectin-9 by Alexandra Brooks and coworkers.3
Their Figure caption reads:
Figure 10. Proposed model for Kynurenine Pathway activation in the brain. Multiple studies have shown that in vivo administration of LPS or pI:C to mice increased peripheral pro-inflammatory cytokines (including IFNγ, TNFα, and IL-1β). These circulating cytokines, as well as immune cells that produce them, can enter the brain, to stimulate brain parenchymal production of additional immunomodulatory agents (cytokines and galectins). Gal-9 (produced within the brain or from the circulation) and IFNγ (from the circulation or infiltrating immune cells) synergize to increase expression of DO transcripts in the brain. Ex vivo, IFNγ is added [since brain parenchyma (i.e., OHSCs) does not express this cytokine], Gal-9 is also added to directly test its activity (but Gal-9 is expressed by cells resident to the brain). Independent of the source, IFNγ and Gal-9 increase DO expression in a DO- and transcript-specific manner, modeling in vivo responses. DO induction would increase flux down the Kynurenine Pathway to serve two purposes: supplying NAD+ for the brain, but with consequences (metabolites Kyn, KynA, and QuinA, modulate behavior and immune activity).
Here DO = Dioxygenase, LPS = Endotoxin, pI:C = Polyinosinic:polycytidylic acid (commonly used to mimic viral double stranded RNA, see my article showing it is commonly contaminated with Endotoxin4 ), Kyn = Kynurenine, KynA = Kynurenic Acid, QuinA = Quinolinic Acid (The Universal Neurotoxin5 ), OHSCs = Organotypic Hippocampal Slice Cultures, IFNγ = Interferon Gamma, TNFα = Tumor Necrosis Factor Alpha, IL-1β = Interleukin 1 Beta also known as the Apical Cytokine, Nicotinamide Adenine Dinucleotide = NAD+
Fatigue linked to Galectin-9
Endotoxin causes Fatigue and Headache.6
A recent paper7 reported:
the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts.
Alzheimer’s Amyloid Protein stimulates Galection-9
Previously I wrote about Endotoxin and Alzheimer’s Disease.8
A recent paper9 showed that injection of Amyloid Protein into the Brain stimulates Galectin-9 causing reduced cognitive function.
Brain Fog linked to Galectin-9
In adolescents exposed perinatally to HIV, reduced cognitive ability is associated with Galectin-9 levels.10
Pre-eclampsia linked to Galectin-9
A recent study11 from China found “CD11chigh dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.”
Breast Cancer Driven by Galectin-9
Galectin-9 increases the invasiveness of Breast Cancer.12
Good news for Liver Transplant Recipients?
Higher levels of Galectin-9 were associated with improved Liver Transplant Tolerance after withdrawal of immunosuppressive treatments.13
Galectin-9 and Autoimmune Disease
Patients with Systemic Lupus Erythematosus (SLE) have high levels of serum14 Galectin-9. This is not surprising because many disease proceed via Endotoxin induced IFNγ.
Reached the email length limit, so I will add more references later.
Alexandra K. Brooks Marcus A. Lawson, Jennifer L. Rytych, Kevin C. Yu, Tiffany M. Janda, Andrew J. Steelman and Robert H. McCusker. 2016. Immunomodulatory Factors Galectin-9 and Interferon-Gamma Synergize to Induce Expression of Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Hippocampus. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00422/full
Berentschot JC, et al . 2023. Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1254899/full
Eleazar Ramírez Hernandez, Luis Fernando Hernandez Zimbron , Emmanuel Segura Perez, Jose Luis Sanchez Salgado , Mohamed Ali Pereyra Morales , Edgar Zenteno. 2024. Galectin-9 and Tim-3 are upregulated in response to microglial activation induced by the peptide Amyloid-β (25–35). https://www.sciencedirect.com/science/article/pii/S0143417924000258
Moar, Preeti; Linn, Kyaw; Premeaux, Thomas A.; Bowler, Scott; Sardarni, Urvinder Kaur; Gopalan, Bindu Parachalil; Shwe, Ei E.; San, Thidar; Han, Haymar; Clements, Danielle; Hlaing, Chaw S.; Kyu, Ei H.; Thair, Cho; Mar, Yi Y.; Nway, Nway; Mannarino, Julie; Bolzenius, Jacob; Mar, Soe; Aye, Aye Mya M.; Tandon, Ravi; Paul, Robert; Ndhlovu, Lishomwa C. Plasma Galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV. https://journals.lww.com/aidsonline/abstract/9900/plasma_galectin_9_relates_to_cognitive_performance.477.aspx
Yanhong Li, Yifei Sang,, Yunjian Chang, Chunfang Xu, Yikong Lin, Yao Zhang, Philip C.N. Chiu, William S.B. Yeung, Haisheng Zhou, Ningzheng Dong, Ling Xu, Jiajia Chen, Weijie Zhao, Lu Liu, Di Yu, Xingxing Zang, Jiangfeng Ye, Jinying Yang, Qingyu Wu, Dajin Li, Ligang Wu and Meirong Du. 2024. A Galectin-9–Driven CD11chigh Decidual Macrophage Subset Suppresses Uterine Vascular Remodeling in Preeclampsia. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064391
Dharma Pally, Mallar Banerjee, Shahid Hussain, Rekha V. Kumar, Alexandra Petersson, Ebba Rosendal, Ludvig Gunnarsson, Kristoffer Peterson, Hakon Leffler, Ulf J. Nilsson, and Ramray Bhat. Galectin-9 Signaling Drives Breast Cancer Invasion through Extracellular Matrix. https://pubs.acs.org/doi/10.1021/acschembio.1c00902
Nguyen Hai Nam, Kojiro Taura, Yukinori Koyama, Takahiro Nishio, Gen Yamamoto, Yusuke Uemoto, Yusuke Kimura, Li Xuefeng, Daichi Nakamura, Kenji Yoshino, Eri Ogawa, Tatsuya Okamoto, Atsushi Yoshizawa, Satoru Seo, Keiko Iwaisako, Tomoaki Yoh, Koichiro Hata, Toshihiko Masui, Hideaki Okajima, Hironori Haga, Shinji Uemoto, Etsuro Hatano. 2021. https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/lt.26336
Mehta P, et al. 2022. Serum and urinary galectin-9 and C-X-C motif chemokine ligand 10. https://journals.sagepub.com/doi/abs/10.1177/09612033221082907