Differential Expression of Matrix Metalloproteinases 2, 9 and Cytokines by Neutrophils and Monocytes in the Clinical Forms of Chagas Disease

Abstract

Dilated cardiomyopathy, the most severe manifestation in chronic phase of Chagas disease, affects about 30% of patients and is characterized by myocardial dysfunction and interstitial fibrosis due to extracellular matrix (ECM) remodeling. ECM remodeling is regulated by proteolytic enzymes such as matrix metalloproteinases (MMPs) and cytokines produced by immune cells, including phagocytes. We evaluated by flow cytometry the expression of MMP-2, MMP-9, IL-1β, TNF-α, TGF-β and IL-10 by neutrophils and monocytes from patients with indeterminate (IND) and cardiac (CARD) clinical forms of Chagas disease and non-infected individuals (NI), before and after in vitro stimulation with Trypanosoma cruzi antigens. Our results showed an important contribution of neutrophils for MMPs production, while monocytes seemed to be involved in cytokine production. The results showed that neutrophils and monocytes from IND and CARD patients had higher intracellular levels of MMP-2 and MMP-9 than NI individuals. On the other hand, T. cruzi derived-antigens promote a differential expression of MMP-2 and MMP-9 in patients with Chagas disease and may regulate MMPs expression in neutrophils and monocytes, mainly when a cardiac alteration is not present. Our data also showed that in the presence of T. cruzi derived-antigens the production of cytokines by neutrophils and monocytes, but mainly by monocytes, may be intensified. Correlation analysis demonstrated that MMP-2 had a positive correlation with IL-10 and a negative correlation with IL-1β, whereas MMP-9 showed a negative correlation with IL-10. We also observed that IND patients presented a greater percentage of high producer cells of regulatory molecules when compared to CARD patients, indicating a different pattern in the immune response. Our data suggest that MMPs and cytokines produced by neutrophils and monocytes are important contributors for cardiac remodeling and may be an interesting target for new biomarker research.

Involvement of neutrophils in Chagas disease pathology

“…Monocytes and neutrophils of indeterminate chagasic patients produce more MMP‐2, TGF‐β and IL‐10, and all regulatory molecules, than monocytes and neutrophils from cardiac chagasic patients. The last cells produce more MMP‐9, TNF‐α and IL‐1β, and all inflammatory molecule . This suggests that innate immunity cells may be directly contributing to cardiac muscle remodelling, as well as to the establishment of the clinical forms of Chagas disease.…”

“…The last cells produce more MMP-9, TNF-α and IL-1β, and all inflammatory molecule. 54 This suggests that innate immunity cells may be directly contributing to cardiac muscle remodelling, as well as to the establishment of the clinical forms of Chagas disease.…”

La respuesta inmunitaria adaptativa en la infección crónica por Trypanosoma cruzi

“…En pacientes con infección crónica por T. cruzi también se ha descrito un aumento de las metaloproteinasas 2 (MMP2) y 9 (MMP9) en neutrófilos y monocitos, comparadas con las de individuos no infectados, aunque sin diferencias significativas entre asintomáticos y sintomáticos. Estas enzimas, que participan en el remodelamiento tisular, podrían estar asociadas al daño cardiaco (Medeiros, et al, 2017) En niños en fase asintomática temprana se ha determinado que el número de células NK y de monocitos inflamatorios (CD14+ CD16+ HLA-DR++) en sangre periférica aumenta en comparación con individuos no infectados. En estas poblaciones, cuyos valores pueden volver a niveles basales en sangre periférica en la infección crónica, se han asociado al mantenimiento de la fase asintomática (Vitelli-Avelar, et al, 2006).…”

Design, Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors

“…[6,21] Gelatinases play ac entral role in the degradation of collagen types IV,V ,V II and Xa nd gelatin and are expressed in many cells andt issues, including skin, fibroblasts, keratinocytes,c hondrocytes, endothelial cells and monocytes. [22] They are involved in almost all phases of tumour progression, from tumour developmentt om etastasis. However, our attention was slightly shifted to MMP-2, which is involved in endometrial menstrual breakdown, regulation of vascularisa-Ta rgeting matrix metalloproteinases (MMPs) is ap ursued strategy for treatings everal pathological conditions, such as multiple sclerosisa nd cancer.…”