Immunomodulatory role of Th17 pathway in experimental visceral leishmaniasis

Khatonier, R; Ahmed, Giasuddin; Sarmah, Pallab; Narain, Kanwar; Khan, Abdul Mabood

doi:10.1016/j.imbio.2021.152148

Cited by 9 publications

(7 citation statements)

References 68 publications

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“…The Th17 subsets of T cells contribute to a protective immune response against VL. This protection is mainly mediated by the secretion of IL-17 and neutrophil infiltration [ 66 , 67 ]. At the early phase of VL infection, a strong IL-17 response was observed, followed by a progressive reduction to basal level during chronic VL, due to suppression by Treg lymphocytes [ 68 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

Diotallevi,

Bruno,

Castelli

et al. 2024

PLoS Negl Trop Dis

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Background In the Mediterranean basin, three Leishmania species have been identified: L. infantum, L. major and L. tropica, causing zoonotic visceral leishmaniasis (VL), zoonotic cutaneous leishmaniasis (CL) and anthroponotic CL, respectively. Despite animal models and genomic/transcriptomic studies provided important insights, the pathogenic determinants modulating the development of VL and CL are still poorly understood. This work aimed to identify host transcriptional signatures shared by cells infected with L. infantum, L. major, and L. tropica, as well as specific transcriptional signatures elicited by parasites causing VL (i.e., L. infantum) and parasites involved in CL (i.e., L. major, L. tropica). Methodology/Principal findings U937 cells differentiated into macrophage-like cells were infected with L. infantum, L. major and L. tropica for 24h and 48h, and total RNA was extracted. RNA sequencing, performed on an Illumina NovaSeq 6000 platform, was used to evaluate the transcriptional signatures of infected cells with respect to non-infected cells at both time points. The EdgeR package was used to identify differentially expressed genes (fold change > 2 and FDR-adjusted p-values < 0.05). Then, functional enrichment analysis was employed to identify the enriched ontology terms in which these genes are involved. At 24h post-infection, a common signature of 463 dysregulated genes shared among all infection conditions was recognized, while at 48h post-infection the common signature was reduced to 120 genes. Aside from a common transcriptional response, we evidenced different upregulated functional pathways characterizing L. infantum-infected cells, such as VEGFA-VEGFR2 and NFE2L2-related pathways, indicating vascular remodeling and reduction of oxidative stress as potentially important factors for visceralization. Conclusions The identification of pathways elicited by parasites causing VL or CL could lead to new therapeutic strategies for leishmaniasis, combining the canonical anti-leishmania compounds with host-directed therapy.

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Section: Resultsmentioning

confidence: 99%

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

Diotallevi,

Bruno,

Castelli

et al. 2024

PLoS Negl Trop Dis

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“…Further investigation revealed higher mRNA levels of cytokines such as IL‐12, IL‐6, IL‐23, and IL‐1 in PA28γ‐overexpressing keratinocytes compared to control cells, along with elevated protein levels of IL‐12 and IL‐6 in their supernatant. These cytokines are known to promote the development and activity of Th1 and Th17 cells, 38 , 39 indicating that PA28γ‐overexpressing keratinocytes can release cytokines associated with the differentiation of CD4 + T‐cells into Th1 and Th17 cells, thereby stimulating T‐cell immune responses.…”

Section: Discussionmentioning

confidence: 99%

PA28γ induces dendritic cell maturation and activates T‐cell immune responses in oral lichen planus

Wang,

Zhang,

Deng

et al. 2024

MedComm

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Oral lichen planus (OLP) is a common chronic inflammatory disease of the oral mucosa, the mechanism of its inflammatory progression has not yet been fully elucidated. PA28γ plays a significant role in a variety of immune‐related diseases. However, the exact role of PA28γ in the pathogenesis of OLP remains unclear. Here, we demonstrated that PA28γ is overexpressed in epithelial cells and inflammatory cells of OLP tissues but has no significant relationship with OLP subtypes. Functionally, keratinocytes with high PA28γ expression could induce dendritic cell (DC) maturation and promote the T‐cell differentiation into Th1 cells in response to the immune response. In addition, we found that a high level of PA28γ expression is associated with high numbers of infiltrating mature DCs and activated T‐cells in OLP tissues. Mechanistically, keratinocytes with high PA28γ expression could promote the secretion of C–C motif chemokine (CCL)5, blocking CCL5 or/and its receptor CD44 could inhibit the induction of T‐cell differentiation by keratinocytes with high PA28γ expression. In conclusion, we reveal that keratinocytes with high expression of PA28γ in OLP can induce DC maturation and promote T‐cell differentiation through the CCL5‐CD44 pathway, providing previously unidentified mechanistic insights into the mechanism of inflammatory progression in OLP.

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“…Moreover, DEGs in BMDCs hosting fixed parasites suggested that these cells lead to differentiation of T cells into Th17 subpopulation by the increased levels of il6 and il23 genes found. It is known that IL-6 along with TGF-β induce the development and maintenance of Th17 effector cells through upregulation of the IL-23 cytokine and its receptors [ 89 ], which have been associated with protection against visceral leishmaniasis [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Leishmania infantum Infected Dendritic Cells: Insights into the Role of Immunometabolism in Host-Parasite Interaction

et al. 2022

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Leishmania parasites are capable of effectively invading dendritic cells (DCs), a cell population orchestrating immune responses against several diseases, including leishmaniasis, by bridging innate and adaptive immunity. Leishmania on the other hand has evolved various mechanisms to subvert DCs activation and establish infection. Thus, the transcriptional profile of DCs derived from bone marrow (BMDCs) that have been infected with Leishmania infantum parasite or of DCs exposed to chemically inactivated parasites was investigated via RNA sequencing, aiming to better understand the host–pathogen interplay. Flow cytometry analysis revealed that L. infantum actively inhibits maturation of not only infected but also bystander BMDCs. Analysis of double-sorted L. infantum infected BMDCs revealed significantly increased expression of genes mainly associated with metabolism and particularly glycolysis. Moreover, differentially expressed genes (DEGs) related to DC-T cell interactions were also found to be upregulated exclusively in infected BMDCs. On the contrary, transcriptome analysis of fixed parasites containing BMDCs indicated that energy production was mediated through TCA cycle and oxidative phosphorylation. In addition, DEGs related to differentiation of DCs leading to activation and differentiation of Th17 subpopulations were detected. These findings suggest an important role of metabolism on DCs-Leishmania interplay and eventually disease establishment.

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Immunomodulatory role of Th17 pathway in experimental visceral leishmaniasis

Cited by 9 publications

References 68 publications

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

Transcriptional signatures in human macrophage-like cells infected by Leishmania infantum, Leishmania major and Leishmania tropica

PA28γ induces dendritic cell maturation and activates T‐cell immune responses in oral lichen planus

Transcriptional Profiling of Leishmania infantum Infected Dendritic Cells: Insights into the Role of Immunometabolism in Host-Parasite Interaction

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