Deficiency of CD73 activity promotes protective cardiac immunity against Trypanosoma cruzi infection but permissive environment in visceral adipose tissue

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Eberhardt, Natalia^1,2  Maria Sanmarco, Liliana^1,2,5  Bergero, Gaston^1,2  Gustavo Theumer, Martin^1,2  Cristina Garcia, Monica³  Eric Ponce, Nicolas¹  Carolina Cano, Roxana^2,4  Pilar Aoki, Maria^1,2 

[1] Consejo Nacl Invest Cient & Tecnol CONICET, Ctr Invest Bioquim Clin & Inmunol CIBICI, Cordoba, Argentina

[2] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Cordoba, Argentina

[3] Univ Nacl Cordoba, Consejo Nacl Invest Cient & Tecnol CONICET, Unidad Tecnol Farmaceut UNITEFA, Dept Ciencias Farmaceut,Fac Ciencias Quim, Cordoba, Argentina

[4] Univ Nacl Cordoba, Consejo Nacl Invest Cient & Tecnol CONICET, Unidad Asociada Area Ciencias Agr Ingn Ciencias B, Fac Ciencias Quim, Cordoba, Argentina

[5] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

关键词: CD73;    CD39;    Extracellular ATP;    Adenosine;    Chagas disease;    Purinergic signaling;   

DOI  :  10.1016/j.bbadis.2019.165592

来源: Elsevier

【 摘 要 】

Damaged cells release the pro-inflammatory signal ATP, which is degraded by the ectonucleotidases CD39 and CD73 to the anti-inflammatory mediator adenosine (ADO). The balance between ATP/ADO is known to determine the outcome of inflammation/infection. However, modulation of the local immune response in different tissues due to changes in the balance of purinergic metabolites has yet to be investigated. Here, we explored the contribution of CD73-derived ADO on the acute immune response against Trypanosoma cruzi parasite, which invades and proliferates within different target tissues. Deficiency of CD73 activity led to an enhanced cardiac microbicidal immune response with an augmented frequency of macrophages with inflammatory phenotype and increased CD8 + T cell effector functions. The increment of local inducible nitric oxide (NO) synthase (iNOS) + macrophages and the consequent rise of myocardial NO production in association with reduced ADO levels induced protection against T. cruzi infection as observed by the diminished cardiac parasite burden compared to their wild-type (WT) counterpart. Unexpectedly, parasitemia was substantially raised in CD73KO mice in comparison with WT mice, suggesting the existence of tissue reservoir/s outside myocardium. Indeed, CD73KO liver and visceral adipose tissue (VAT) showed increased parasite burden associated with a reduced ATP/ADO ratio and the lack of substantial microbicidal immune response. These data reveal that the purinergic system has a tissue-dependent impact on the host immune response against T. cruzi infection.

【 授权许可】

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