Modulation of fibroblast behavior by Leishmania: a pathway to understanding disease progression in cutaneous leishmaniasis

Leishmaniasis is a parasitic infection caused by obligatory intracellular protozoa of the Leishmania genus. Macrophages are the main cell for Leishmania parasites that play a key role in immune response against it. Interestingly, both the promastigote and amastigote forms of the parasite have also been detected in fibroblasts, revealing the complex interactions during the infection. Cutaneous leishmaniasis, caused by different Leishmania species, presents different clinical outcomes, largely influenced by the interactions between the parasite and host immune cells. This study aimed to determine how macrophages infected by Leishmania amazonensis or L. braziliensis, obtained from different clinical forms, modulate the response of dermal fibroblasts in an in vitro model. Our research shows that after 24 h; fibroblast migration was reduced by 1.5-fold with conditioned medium from L. braziliensis-infected macrophages. After 48 h, the G1-phase in fibroblasts was reduced by up to 54% compared to controls. Fibroblasts treated with L. amazonensis-infected macrophages showed a 75% decrease in MMP-2 activity at 24 h and 44% at 48 h, while L. braziliensis-treated fibroblasts showed a 24% decrease. IL-6 levels were significantly lower (91% for L. amazonensis and 84% for L. braziliensis) in fibroblasts after 24 h, with IL-6 increasing 1.6-fold in L. amazonensis-treated fibroblasts after 48 h. Correlation analysis showed that TNF-α levels were strongly negatively correlated with wound size, while IL-6 levels were negatively correlated with MMP-9 activity. These findings suggest that L. amazonensis promotes tissue repair through reduced MMP-2 activity and lower IL-6, whereas L. braziliensis enhances inflammation and extracellular matrix remodeling. In conclusion, this study highlights the pivotal role of fibroblasts as active participants in the immune response to Leishmania, with L. amazonensis promoting a more favorable environment for tissue repair and L. braziliensis promoting inflammation and tissue damage. This knowledge on host-Leishmania interactions could help improve knowledge of chronic or asymptomatic infections lead to more well-defined and efficient responses for controlling cutaneous leishmaniasis.