RESUMO
Obesity is a global pandemic associated with several comorbidities, such as cardiovascular diseases and type 2 diabetes. It is also a predisposing factor for infectious diseases, increasing mortality rates. Moreover, diet-induced obesity can cause metabolic fluctuations that affect macrophage differentiation in various organs. In this sense, we investigated how bone marrow-derived macrophages and tissue-resident macrophages in the skin, which have been differentiated in a host with metabolic syndrome and with previous inflammatory burden, respond to Leishmania major infection. Our findings suggest that bone marrow-derived macrophages from obese C57BL/6 mice, even when cultivated in vitro with inflammatory stimuli, are more susceptible to L. major. These macrophages produce less tumor necrosing factor (TNF) and nitric oxide (NO) and show higher arginase activity. Furthermore, obese mice infected with an intermediate dose of L. major in the skin had more severe lesions when analyzed for ulceration, diameter, thickness, and parasite burden. The increase in lesion severity in obese mice was associated with a higher frequency of tissue-resident macrophages, which are less efficient in killing parasites. We also used CCR2-/- mice, which predominantly have tissue-resident macrophages, and found that lesion resolution was delayed in association with CCR2 deficiency. Additionally, obesity potentiated tissue damage, resulting in higher frequency of tissue-resident macrophages. Our results demonstrate that obesity can alter macrophage responses to infection, leading to increased susceptibility to L. major and more severe cutaneous leishmaniasis. These findings may have important implications for managing obesity-related infections and the development of new therapies for cutaneous leishmaniasis.
RESUMO
Despite presenting a worse prognosis and being associated with highly aggressive tumors, triple-negative breast cancer (TNBC) is characterized by the higher frequency of tumor-infiltrating lymphocytes, which have been implicated in better overall survival and response to therapy. Though recent studies have reported the capacity of B lymphocytes to recognize overly-expressed normal proteins, and tumor-associated antigens, how tumor development potentially modifies B cell response is yet to be elucidated. Our findings reveal distinct effects of 4T1 and E0771 murine tumor development on B cells in secondary lymphoid organs. Notably, we observe a significant expansion of total B cells and plasma cells in the tumor-draining lymph nodes (tDLNs) as early as 7 days after tumor challenge in both murine models, whereas changes in the spleen are less pronounced. Surprisingly, within the tumor microenvironment (TME) of both models, we detect distinct B cell subpopulations, but tumor development does not appear to cause major alterations in their frequency over time. Furthermore, our investigation into B cell regulatory phenotypes highlights that the B10 Breg phenotype remains unaffected in the evaluated tissues. Most importantly, we identified an increase in CD19 + LAG-3 + cells in tDLNs of both murine models. Interestingly, although CD19 + LAG-3 + cells represent a minor subset of total B cells (< 3%) in all evaluated tissues, most of these cells exhibit elevated expression of IgD, suggesting that LAG-3 may serve as an activation marker for B cells. Corroborating with these findings, we detected distinct cell cycle and proliferation genes alongside LAG-3 analyzing scRNA-Seq data from a cohort of TNBC patients. More importantly, our study suggests that the presence of LAG-3 B cells in breast tumors could be associated with a good prognosis, as patients with higher levels of LAG-3 B cell transcripts had a longer progression-free interval (PFI). This novel insight could pave the way for targeted therapies that harness the unique properties of LAG-3 + B cells, potentially offering new avenues for improving patient outcomes in TNBC. Further research is warranted to unravel the mechanistic pathways of these cells and to validate their prognostic value in larger, diverse patient cohorts.