Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease.
Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH.
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. ariasloste@gmail.com.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. ariasloste@gmail.com.
María Teresa
MT
Arias-Loste
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. piruzubieta@gmail.com.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. piruzubieta@gmail.com.
Paula
P
Iruzubieta
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. anpuente@humv.es.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. anpuente@humv.es.
Ángela
Á
Puente
Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. david.ramos.m@gmail.com.
David
D
Ramos
Transplant and Autoimmunity Group, Research Institute Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain. loraksc@gmail.com.
Carolina
C
Santa Cruz
Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. aesga@hotmail.com.
Ángel
Á
Estébanez
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. susanallerena@hotmail.com.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. susanallerena@hotmail.com.
Susana
S
Llerena
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. maika_1387@hotmail.com.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. maika_1387@hotmail.com.
Carmen
C
Alonso-Martín
Transplant and Autoimmunity Group, Research Institute Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain. david_san_segundo@hotmail.com.|Immunology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. david_san_segundo@hotmail.com.
David
D
San Segundo
Transplant and Autoimmunity Group, Research Institute Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain. lorenalvar@hotmail.com.
Lorena
L
Álvarez
General Surgery Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. alopez@humv.es.
Antonio
A
López Useros
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. digfge@humv.es.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. digfge@humv.es.
Emilio
E
Fábrega
Transplant and Autoimmunity Group, Research Institute Marqués de Valdecilla (IDIVAL), 39008 Santander, Spain. mlopezhoyos@humv.es.|Immunology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. mlopezhoyos@humv.es.
Marcos
M
López-Hoyos
Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain. javiercrespo1991@gmail.com.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), 390008 Santander, Spain. javiercrespo1991@gmail.com.
Javier
J
Crespo
D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism*; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000378:metabolism*
D016207:Cytokines; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6
TLR2; TLR6; lobular inflammation; morbid obesity; non-alcoholic fatty liver disease; pro-inflammatory cytokines