Chagas disease, a neglected disease caused by the protozoan Trypanosoma cruzi, is endemic in 21 Latin American countries, affecting 6–8 million people. Increasing numbers of Chagas disease cases have also been reported in non-endemic countries due to migration, contamination via blood transfusions or organ transplantation, characterizing Chagas as an emerging disease in such regions. While most individuals in the chronic phase of Chagas disease remain in an asymptomatic clinical form named indeterminate, approximately 30% of the patients develop a cardiomyopathy that is amongst the deadliest cardiopathies known. The clinical distinctions between the indeterminate and the cardiac clinical forms are associated with different immune responses mediated by innate and adaptive cells. In this review, we present a collection of studies focusing on the human disease, discussing several aspects that demonstrate the association between chemokines, cytokines, and cytotoxic molecules with the distinct clinical outcomes of human infection with Trypanosoma cruzi. In addition, we discuss the role of gene polymorphisms in the transcriptional control of these immunoregulatory molecules. Finally, we discuss the potential application of cytokine expression and gene polymorphisms as markers of susceptibility to developing the severe form of Chagas disease, and as targets for disease control.

Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sb^v), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sb^v alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4⁺ and CD8⁺ cells were not different before and after treatments or comparing different treatments, frequency of CD68⁺ cells decreased after treatment with Sb^v + PTX, but not with Sb^v. This was due to a reduction in CD68⁺ TNF-alpha⁺ and not in CD68⁺ IL-10⁺ cells. The frequency of TNF-alpha⁺ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sb^v + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sb^v + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A⁺ cells. Our data suggest that treatment with Sb^v + PTX acts in CD68⁺ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.

The release of DNA to the extracellular milieu is a biological process referred to as etosis, which is involved in both physiological and pathological functions. Although the release of DNA extracellular traps (ETs) was initially attributed to innate immune cells such as neutrophils, eosinophils, and macrophages, recent studies have shown that T cells, as well as non-immune cells, are capable of releasing ETs. These structures were described primarily for their potential to trap and kill pathogens, presenting an important strategy of host defense. Intriguingly, these functions have been associated with intracellular pathogens such as the parasites Leishmania sp. and Trypanosoma cruzi, causative agents of leishmaniasis and Chagas disease, respectively. These are two devastating tropical diseases that lead to thousands of deaths every year. In an apparent contradiction, ETs can also induce and amplify inflammation, which may lead to worsening disease pathology. This has prompted the concept of targeting ETs’ release as a means of controlling tissue destruction to treat human diseases. What is the best approach to prevent disease severity: inducing ETs to kill pathogens or preventing their release? In this Perspective article, we will discuss the importance of understanding ETs released by different cell types and the need to balance their potentially complementary functions. In addition, we will explore other functions of ETs and their translational applications to benefit individuals infected with intracellular parasites and other pathogens. Ultimately, a better understanding of the role of ETs in disease pathogenesis will provide valuable insights into developing novel therapies for human diseases.

American Tegumentary Leishmaniasis (ATL), caused by parasites of the genus Leishmania, presents a significant global health challenge, especially in Brazil, where cutaneous and mucosal forms are highly prevalent. Cutaneous Leishmaniasis (CL) typically results in single lesions, while mucosal Leishmaniasis (ML) leads to destructive mucosal lesions with a worse prognosis. The immune response, regulated by cytokines, plays a crucial role in disease progression and resolution. In CL, a balance between pro-inflammatory and anti-inflammatory cytokines is associated with lesion resolution, whereas in ML, an exaggerated inflammatory response worsens tissue damage. Thus, understanding cytokine regulation is essential for unveiling disease pathology and developing effective immunotherapeutic strategies. Here we discuss gene polymorphisms and epigenetic modifications that affect cytokine expression, influencing disease susceptibility and severity, as well as immunotherapeutic approaches that involve cytokine function in Leishmaniasis. In addition, we examine advancements in drug discovery, utilizing in silico methods and targeted drug delivery systems, providing potential avenues for better therapeutic interventions. Continuous research into immune responses and cytokine production and function is critical for identifying novel therapeutic targets and optimizing patient care for ATL.

The Repulsive Guidance Molecule a (RGMa) is a multifunctional GPI-anchored protein localized in the sarcolemma and sarcoplasm of the adult skeletal muscle cell. Our research group showed that RGMa overexpression can promote myoblast fusion and induce hypertrophic muscle fibers during in vitro differentiation. Here, we report that RGMa is expressed in primary skeletal muscle cells cultured in vitro, showing a nuclear localization, revealed by immunostaining with an antibody targeting its C-terminal region (C-RGMa). While RGMa was detected in the nuclei, its canonical receptor, Neogenin, was predominantly found in the perinuclear region. Nuclear RGMa was absent in Neogenin-knockdown cells, suggesting that Neogenin mediates its nuclear transport. Functional assays suggested that RGMa promotes primary skeletal muscle cell viability and proliferation and supports their myogenic commitment. These findings reveal a previously unrecognized nuclear function of RGMa–Neogenin signaling and provide new insights into the regulation of skeletal muscle cell behavior in vitro.