IL-33/ST2 Signaling Protects the Heart by Restraining Inflammation and Parasite Burden during <i>Trypanosoma cruzi</i> Experimental Infection

Chagas disease (CD), caused by the parasite <i>Trypanosoma cruzi</i>, affects millions of people worldwide and often leads to fatal heart damage. The course of CD is influenced by how the immune system is tuned, which can protect the host and favor parasite persistence. Interleukin-33 (IL-33) is an alarmin released upon tissue injury that signals through the ST2 receptor, exerting context-dependent regulatory or pathogenic effects. However, the role of the IL-33/ST2 axis in <i>T. cruzi</i>-induced myocarditis remains unclear. Here, using ST2-deficient (ST2<sup>-/-</sup>) and wild-type (WT) female mice infected with the <i>T. cruzi</i> Y strain, we investigated its contribution to cardiac inflammation, tissue damage, and parasite burden. We found that ST2 signaling was not essential for controlling parasitemia, but its deficiency led to early onset myocarditis, disorganized fibrosis, and distinct electrical conduction. This severe immunopathology was driven by a remodeling of the cardiac immune landscape, with ST2<sup>-/-</sup> mice exhibiting an influx of IFN-γ-producing monocytes and a shift in resident and monocyte-derived macrophages toward a pathogenic, pro-inflammatory phenotype. Likewise, the cardiac T cell compartment, including both conventional and γδ T cells, was skewed toward an inflammatory, IFN-γ-driven profile. However, infected ST2-deficient mice also displayed higher cardiac parasite burden and impaired nitric oxide production, indicating a dysfunctional response in parasite control. Together, these findings demonstrate that the IL-33/ST2 axis limits early systemic inflammation, orchestrates cardiac immune response, and protects against immunopathology and electrical remodeling during <i>T. cruzi</i> experimental infection. Targeting this pathway may offer therapeutic potential for preventing cardiac damage in CD.

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Publication Details

Journal
ACS Infectious Diseases
Published
2025-12-09
DOI
https://doi.org/10.1021/acsinfecdis.5c00859
Citations
1
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
Field-Weighted Citation Impact
0.80
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article

IL-33/ST2 Signaling Protects the Heart by Restraining Inflammation and Parasite Burden during Trypanosoma cruzi Experimental Infection

Marina Possa dos Reys, Ricardo Toshio Fujiwara, Ana Laura Grossi de Oliveira, Chiara Cássia Oliveira Amorim et al.
1 citations
ACS Infectious Diseases
IL-33, ST2, and ILC Pathways
0.80
article

IL-33/ST2 Signaling Protects the Heart by Restraining Inflammation and Parasite Burden during Trypanosoma cruzi Experimental Infection

Marina Possa dos Reys, Ricardo Toshio Fujiwara, Ana Laura Grossi de Oliveira, Chiara Cássia Oliveira Amorim, Luís Silva, Tatyane Martins Cirilo, Geovanni Dantas Cassali, Isabela de Brito Duval, Luísa Mourão Dias Magalhães, Gabriela Gomes Monteiro Lemos, Leslie Amaral, Artur Santos‐Miranda, Idam de Oliveira‐Junior, Mayra Fernanda Ricci, Lilian Lacerda Bueno, Fabiana S. Machado, Jorge Lucas Nascimento Souza, Inês Melo-Marques, Ana Rafaela Antunes-Porto, Fernando Bento Rodrigues Oliveira, Laura Lis de Oliveira Santos, Lucas Barbosa de Santana, G Silva, Marcelo Eduardo Cardozo, José Bryan da Rocha Rihs
article en
1 citations

Abstract

Chagas disease (CD), caused by the parasite <i>Trypanosoma cruzi</i>, affects millions of people worldwide and often leads to fatal heart damage. The course of CD is influenced by how the immune system is tuned, which can protect the host and favor parasite persistence. Interleukin-33 (IL-33) is an alarmin released upon tissue injury that signals through the ST2 receptor, exerting context-dependent regulatory or pathogenic effects. However, the role of the IL-33/ST2 axis in <i>T. cruzi</i>-induced myocarditis remains unclear. Here, using ST2-deficient (ST2<sup>-/-</sup>) and wild-type (WT) female mice infected with the <i>T. cruzi</i> Y strain, we investigated its contribution to cardiac inflammation, tissue damage, and parasite burden. We found that ST2 signaling was not essential for controlling parasitemia, but its deficiency led to early onset myocarditis, disorganized fibrosis, and distinct electrical conduction. This severe immunopathology was driven by a remodeling of the cardiac immune landscape, with ST2<sup>-/-</sup> mice exhibiting an influx of IFN-γ-producing monocytes and a shift in resident and monocyte-derived macrophages toward a pathogenic, pro-inflammatory phenotype. Likewise, the cardiac T cell compartment, including both conventional and γδ T cells, was skewed toward an inflammatory, IFN-γ-driven profile. However, infected ST2-deficient mice also displayed higher cardiac parasite burden and impaired nitric oxide production, indicating a dysfunctional response in parasite control. Together, these findings demonstrate that the IL-33/ST2 axis limits early systemic inflammation, orchestrates cardiac immune response, and protects against immunopathology and electrical remodeling during <i>T. cruzi</i> experimental infection. Targeting this pathway may offer therapeutic potential for preventing cardiac damage in CD.

ACS Infectious DiseasesVol. 12(1)
Universidade Federal de Minas Gerais (BR), British Institute of International and Comparative Law (GB), Institute of Immunology (HR), Faculdade de Medicina do ABC (BR), Cellular Therapeutics (United Kingdom) (GB), Swiss Institute of Comparative Law (CH), Institute of Parasitology (CZ), Skin Health Institute (AU)
Openalex Percentile: Top 21%
IL-33, ST2, and ILC Pathways
0.80
DOIOpen Access PDFOpenAlex
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