TY - JOUR

T1 - Unique Features of the Immune Response in BTBR Mice

AU - Mutovina, Anastasia

AU - Ayriyants, Kseniya

AU - Mezhlumyan, Eva

AU - Ryabushkina, Yulia

AU - Litvinova, Ekaterina

AU - Bondar, Natalia

AU - Khantakova, Julia

AU - Reshetnikov, Vasiliy

N1 - This work was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement No. 075-10-2021-113, unique project ID RF—193021 × 0001).

PY - 2022/12/8

Y1 - 2022/12/8

N2 - Inflammation plays a considerable role in the pathogenesis of many diseases, including neurodegenerative and psychiatric ones. Elucidation of the specific features of an immune response in various model organisms, and studying the relation of these features with the behavioral phenotype, can improve the understanding of the molecular mechanisms of many psychopathologies. In this work, we focused on BTBR mice, which have a pronounced autism-like behavioral phenotype, elevated levels of oxidative-stress markers, an abnormal immune response, several structural aberrations in the brain, and other unique traits. Although some studies have already shown an abnormal immune response in BTBR mice, the existing literature data are still fragmentary. Here, we used inflammation induced by low-dose lipopolysaccharide, polyinosinic:polycytidylic acid, or their combinations, in mice of strains BTBR T+Itpr3tf/J (BTBR) and C57BL6/J. Peripheral inflammation was assessed by means of a complete blood count, lymphocyte immunophenotyping, and expression levels of cytokines in the spleen. Neuroinflammation was evaluated in the hypothalamus and prefrontal cortex by analysis of mRNA levels of proinflammatory cytokines (tumor necrosis factor, Tnf), (interleukin-1 beta, Il-1β), and (interleukin-6, Il-6) and of markers of microglia activation (allograft inflammatory factor 1, Aif1) and astroglia activation (glial fibrillary acidic protein, Gfap). We found that in both strains of mice, the most severe inflammatory response was caused by the administration of polyinosinic:polycytidylic acid, whereas the combined administration of the two toll-like receptor (TLR) agonists did not enhance this response. Nonetheless, BTBR mice showed a more pronounced response to low-dose lipopolysaccharide, an altered lymphocytosis ratio due to an increase in the number of CD4+ lymphocytes, and high expression of markers of activated microglia (Aif1) and astroglia (Gfap) in various brain regions as compared to C57BL6/J mice. Thus, in addition to research into mechanisms of autism-like behavior, BTBR mice can be used as a model of TLR3/TLR4-induced neuroinflammation and a unique model for finding and evaluating the effectiveness of various TLR antagonists aimed at reducing neuroinflammation.

AB - Inflammation plays a considerable role in the pathogenesis of many diseases, including neurodegenerative and psychiatric ones. Elucidation of the specific features of an immune response in various model organisms, and studying the relation of these features with the behavioral phenotype, can improve the understanding of the molecular mechanisms of many psychopathologies. In this work, we focused on BTBR mice, which have a pronounced autism-like behavioral phenotype, elevated levels of oxidative-stress markers, an abnormal immune response, several structural aberrations in the brain, and other unique traits. Although some studies have already shown an abnormal immune response in BTBR mice, the existing literature data are still fragmentary. Here, we used inflammation induced by low-dose lipopolysaccharide, polyinosinic:polycytidylic acid, or their combinations, in mice of strains BTBR T+Itpr3tf/J (BTBR) and C57BL6/J. Peripheral inflammation was assessed by means of a complete blood count, lymphocyte immunophenotyping, and expression levels of cytokines in the spleen. Neuroinflammation was evaluated in the hypothalamus and prefrontal cortex by analysis of mRNA levels of proinflammatory cytokines (tumor necrosis factor, Tnf), (interleukin-1 beta, Il-1β), and (interleukin-6, Il-6) and of markers of microglia activation (allograft inflammatory factor 1, Aif1) and astroglia activation (glial fibrillary acidic protein, Gfap). We found that in both strains of mice, the most severe inflammatory response was caused by the administration of polyinosinic:polycytidylic acid, whereas the combined administration of the two toll-like receptor (TLR) agonists did not enhance this response. Nonetheless, BTBR mice showed a more pronounced response to low-dose lipopolysaccharide, an altered lymphocytosis ratio due to an increase in the number of CD4+ lymphocytes, and high expression of markers of activated microglia (Aif1) and astroglia (Gfap) in various brain regions as compared to C57BL6/J mice. Thus, in addition to research into mechanisms of autism-like behavior, BTBR mice can be used as a model of TLR3/TLR4-induced neuroinflammation and a unique model for finding and evaluating the effectiveness of various TLR antagonists aimed at reducing neuroinflammation.

KW - Mice

KW - Animals

KW - Neuroinflammatory Diseases

KW - Lipopolysaccharides/toxicity

KW - Mice, Inbred Strains

KW - Cytokines/metabolism

KW - Mice, Inbred C57BL

KW - Inflammation

KW - Interleukin-6

KW - Immunity

KW - Poly C

KW - Disease Models, Animal

KW - Poly I:C

KW - LPS

KW - neuroinflammation

KW - BTBR

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85144542742&origin=inward&txGid=0a4c09ee8f7813e9242c1a52a942e7f3

UR - https://www.mendeley.com/catalogue/28742590-fb5c-3dcb-8a4c-9c419308d39a/

U2 - 10.3390/ijms232415577

DO - 10.3390/ijms232415577

M3 - Article

C2 - 36555219

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 24

M1 - 15577

ER -