Contributions
Abstract: P955
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background and goals: A20 (codified by TNFAIP3 gene) is an ubiquitin-ending enzyme involved in the inhibition of NF-kB and is considered a central gatekeeper in inflammation. Polymorphisms within the TNFAIP3 locus have been associated with autoimmune disorders, such as multiple sclerosis (MS). Recently, we reported a significant down-regulation of A20 in blood cells from MS patients compared to healthy donors due mainly to the monocyte contribution. Based to the importance of myeloid cells in the pathogenesis of MS, we aim to elucidate how the reduced A20 expression in these cells could influence the inflammatory states in vivo.
Methods: The A20lox::CX3CR1 murine model is generated by crossing the A20lox/lox mice with the transgenic mice carrying the Cre recombinase under the control of a specific promoter for myeloid cells including microglia (CX3CR1). Since, the A20lox::CX3CR1 mouse has never been generated before, we characterized their phenotype (A20lox/wt::CX3CR1 heterozygous HT and A20lox/lox::CX3CR1 homozygous KO) compared to their WT littermates (A20wt/wt::CX3CR1). Anatomic-pathological studies were performed in order to evaluate the impact of reducing A20 in myeloid cells.
Results: First, we observed that the HT and the KO mice are viable, but, although the former are fertile, the seconds have a mortality rate of 50%. Female KO have a lower weight compared to both HT and WT, starting already from one month of age. The HT transgenic mice display a decreased weight compared to WT starting from two months of age. Conversely, we did not observe the same results with male mice.
Histological studies revealed some altered features in spleen, liver and glands obtained from 2 months old KO mice. Particularly, a massive hypertrophy of the spleen with expansion of the red pulp showing an increased extra-medullary hematopoietic processes with various degrees of normal differentiation are highlighted in KO mice. Also, spleen architecture is altered by a partial substitution of the white pulp sheaths of lymphoid cells by myeloid cells. Furthermore, liver reported sinusoid dilatation and massive peri-portal and centro-lobular inflammatory infiltrate. Finally, salivary gland of KO mice showed hyperplasia and prominent inflammatory infiltrate surrounding the intercalated ducts.
Conclusions: The phenotypical analysis performed in this murine model suggest that the deficiency of A20 expression in myeloid cells is involved in multi-organs alterations.
Disclosure: The authors have nothing to declare.
Abstract: P955
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Background and goals: A20 (codified by TNFAIP3 gene) is an ubiquitin-ending enzyme involved in the inhibition of NF-kB and is considered a central gatekeeper in inflammation. Polymorphisms within the TNFAIP3 locus have been associated with autoimmune disorders, such as multiple sclerosis (MS). Recently, we reported a significant down-regulation of A20 in blood cells from MS patients compared to healthy donors due mainly to the monocyte contribution. Based to the importance of myeloid cells in the pathogenesis of MS, we aim to elucidate how the reduced A20 expression in these cells could influence the inflammatory states in vivo.
Methods: The A20lox::CX3CR1 murine model is generated by crossing the A20lox/lox mice with the transgenic mice carrying the Cre recombinase under the control of a specific promoter for myeloid cells including microglia (CX3CR1). Since, the A20lox::CX3CR1 mouse has never been generated before, we characterized their phenotype (A20lox/wt::CX3CR1 heterozygous HT and A20lox/lox::CX3CR1 homozygous KO) compared to their WT littermates (A20wt/wt::CX3CR1). Anatomic-pathological studies were performed in order to evaluate the impact of reducing A20 in myeloid cells.
Results: First, we observed that the HT and the KO mice are viable, but, although the former are fertile, the seconds have a mortality rate of 50%. Female KO have a lower weight compared to both HT and WT, starting already from one month of age. The HT transgenic mice display a decreased weight compared to WT starting from two months of age. Conversely, we did not observe the same results with male mice.
Histological studies revealed some altered features in spleen, liver and glands obtained from 2 months old KO mice. Particularly, a massive hypertrophy of the spleen with expansion of the red pulp showing an increased extra-medullary hematopoietic processes with various degrees of normal differentiation are highlighted in KO mice. Also, spleen architecture is altered by a partial substitution of the white pulp sheaths of lymphoid cells by myeloid cells. Furthermore, liver reported sinusoid dilatation and massive peri-portal and centro-lobular inflammatory infiltrate. Finally, salivary gland of KO mice showed hyperplasia and prominent inflammatory infiltrate surrounding the intercalated ducts.
Conclusions: The phenotypical analysis performed in this murine model suggest that the deficiency of A20 expression in myeloid cells is involved in multi-organs alterations.
Disclosure: The authors have nothing to declare.