Charlotte D'Mello1, Wagdi Almishri1, Hongqun Liu2, Mark Gordon Swain3. 1. Immunology Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. 2. Gastrointestinal Research Group and Inflammation Research Network, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. 3. Immunology Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address: swain@ucalgary.ca.
Abstract
BACKGROUND & AIMS: Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury. METHODS: We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile. RESULTS: Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury. CONCLUSIONS: In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms.
BACKGROUND & AIMS:Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury. METHODS: We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile. RESULTS: Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury. CONCLUSIONS: In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms.
Authors: Roosmarijn E Vandenbroucke; Christophe Van Steenkiste; Wouter Claeys; Lien Van Hoecke; Anja Geerts; Hans Van Vlierberghe; Sander Lefere; Griet Van Imschoot; Elien Van Wonterghem; Bart Ghesquière Journal: Sci Rep Date: 2022-10-20 Impact factor: 4.996
Authors: Wagdi Almishri; Rachelle P Davis; Abdel-Aziz Shaheen; Mohammed O Altonsy; Craig N Jenne; Mark G Swain Journal: Front Immunol Date: 2021-03-25 Impact factor: 7.561
Authors: Astrid De Boeck; Bo Young Ahn; Charlotte D'Mello; Xueqing Lun; Shyam V Menon; Mana M Alshehri; Frank Szulzewsky; Yaoqing Shen; Lubaba Khan; Ngoc Ha Dang; Elliott Reichardt; Kimberly-Ann Goring; Jennifer King; Cameron J Grisdale; Natalie Grinshtein; Dolores Hambardzumyan; Karlyne M Reilly; Michael D Blough; J Gregory Cairncross; V Wee Yong; Marco A Marra; Steven J M Jones; David R Kaplan; Kathy D McCoy; Eric C Holland; Pinaki Bose; Jennifer A Chan; Stephen M Robbins; Donna L Senger Journal: Nat Commun Date: 2020-10-05 Impact factor: 14.919