IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease.

Jimena Rada,Gerardo A Mirkin,Azul V Pieralisi,Ricardo Gelpi,Ágata C Cevey,Federico N Penas,Martín Donato,Catalina Alba Soto,Nora B Goren

doi:10.3389/fimmu.2020.572178

Abstract

IL-10 is an anti-inflammatory cytokine that plays a significant role in the modulation of the immune response in many pathological conditions, including infectious diseases. Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, results in an ongoing inflammatory response that may cause heart dysfunction, ultimately leading to heart failure. Given its infectious and inflammatory nature, in this work we analyzed whether the lack of IL-10 hinders the anti-inflammatory effects of fenofibrate, a PPARα ligand, in a murine model of Chagas heart disease (CHD) using IL-10 knockout (IL-10 KO) mice. Our results show fenofibrate was able to restore the abnormal cardiac function displayed by T. cruzi-infected mice lacking IL-10. Treatment with fenofibrate reduced creatine kinase (CK) levels in sera of IL-10 KO mice infected with T. cruzi. Moreover, although fenofibrate could not modulate the inflammatory infiltrates developing in the heart, it was able to reduce the increased collagen deposition in infected IL-10 KO mice. Regarding pro-inflammatory mediators, the most significant finding was the increase in serum IL-17. These were reduced in IL-10 KO mice upon fenofibrate treatment. In agreement with this, the expression of RORγt was reduced. Infection of IL-10 KO mice increased the expression of YmI, FIZZ and Mannose Receptor (tissue healing markers) that remained unchanged upon treatment with fenofibrate. In conclusion, our work emphasizes the role of anti-inflammatory mechanisms to ameliorate heart function in CHD and shows, for the first time, that fenofibrate attains this through IL-10-dependent and -independent mechanisms.

Highlights

Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, triggers both innate [1,2,3], and adaptive [4,5,6] immune responses that aim at the control of the parasite load both in tissues and peripheral blood [Reviewed in [7]]
In this work we study the consequences of IL-10 depletion on the effects of fenofibrate on cardiac function, proinflammatory response and heart remodeling in a model of Chagas heart disease (CHD) resembling Chagasic Cardiomyopathy (CCC)
IL-10 knockout and wild type (WT) mice were infected with the K98 clone of T. cruzi, in order to evaluate the role IL-10 on the effects of fenofibrate treatment in an experimental model of Chagas disease

Summary

Introduction

Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, triggers both innate [1,2,3], and adaptive [4,5,6] immune responses that aim at the control of the parasite load both in tissues and peripheral blood [Reviewed in [7]]. These mechanisms do not succeed in the complete eradication of the parasite, which results in parasite persistence [8,9,10,11,12]. Despite the low levels of parasite load observed during the chronic phase of infection, its persistence plays a crucial role to uphold the inflammatory reaction leading to heart anomalies and remodeling [10, 20]

Methods

Results

Conclusion