Inhibition of gamma-secretase activity without interfering in Notch signalling decreases inflammatory response in patients with cutaneous leishmaniasis

Nascimento, Maurício T.; Franca, Mônica; Carvalho, Augusto M.; Amorim, Camila Farias; Peixoto, Fábio; Beiting, Daniel P.; Scott, Phillip; Carvalho, Edgar M.; Carvalho, Lucas P.

doi:10.1080/22221751.2021.1932608

Cited by 3 publications

(2 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The other half of the biopsies from both DL and CL patients (approximately 150 mg per half fragment) were cultured in polypropylene tubes with 1 mL of complete RPMI at 37 °C and 5% CO 2 for 72 h [ 30 ], and the supernatants were collected and frozen at −80 °C to posteriorly measure GzB production. Supernatants from PBMC, biopsies cultures, and co-cultures from CL and DL patients were collected to determine GzB by ELISA (DuoSet ® ELISA Development System R&D Systems, Minneapolis, MN, USA), as previously described [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Abreu,

Nascimento,

Bacellar

et al. 2024

Pathogens

Self Cite

View full text Add to dashboard Cite

Disseminated leishmaniasis (DL) caused by L. braziliensis is characterized by the presence of 10 to more than 1000 lesions spread on the body. While protection against Leishmania is mediated by macrophages upon activation by IFN-γ produced by CD4+T cells, the pathology of disseminated leishmaniasis (DL) could be mediated by macrophages, NK, and CD8+T cells. Herein, we evaluate the participation of senescent CD8+T cells in the pathogenesis of DL. Methods: Peripheral blood mononuclear cells (PBMCs), biopsies, co-cultures of CD8+T cells with uninfected and infected macrophages (MØ), and PBMC cultures stimulated with soluble L. braziliensis antigen (SLA) for 72 h from patients with cutaneous leishmaniasis (CL) and DL were used to characterize senescent CD8+T cells. Statistical analysis was performed using the Mann–Whitney and Kruskal–Wallis tests, followed by Dunn’s. Results: Patients with DL have an increase in the frequency of circulating CD8+T cells that present a memory/senescent phenotype, while lesions from DL patients have an increase in the frequency of infiltrating CD8+T cells with a senescent/degranulation phenotype. In addition, after specific stimuli, DL patients’ circulating CD8+T with memory/senescent profile, showing degranulation characteristics, increased upon SLA stimuli, and those specific CD8+T cells from DL patients had an increased degranulation phenotype, causing more apoptosis of infected target cells. Conclusions: DL patients show a higher frequency of cytotoxic senescent CD8+T cells compared to CL patients, and that could promote the lysis of infected cells, although without parasite killing, releasing Leishmania to the extracellular compartment, contributing to the spread of parasites.

show abstract

Section: Methodsmentioning

confidence: 99%

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Abreu,

Nascimento,

Bacellar

et al. 2024

Pathogens

Self Cite

View full text Add to dashboard Cite

show abstract

“…An isolate of L. braziliensis (MHOM/BR/LTCP11245) was obtained from a skin lesion of a CL patient and identified as L. braziliensis by multilocus enzyme electrophoresis ( Polari et al., 2019 ; Nascimento et al, 2021 ). Following isolation, parasites were cryopreserved in frozen nitrogen until use.…”

Section: Methodsmentioning

confidence: 99%

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Downregulates the Inflammatory Response in Cutaneous Leishmaniasis Patients Without Interfering in Leishmania braziliensis Killing by Monocytes

Nascimento

Cordeiro

Abreu

et al. 2022

Front. Cell. Infect. Microbiol.

Self Cite

View full text Add to dashboard Cite

Patients with cutaneous leishmaniasis (CL) due to Leishmania braziliensis infection have an exacerbated inflammatory response associated with tissue damage and ulcer development. An increase in the rate of patients who fail therapy with pentavalent antimony has been documented. An adjuvant therapy with an anti-inflammatory drug with the potential of Leishmania killing would benefit CL patients. The aim of the present study was to investigate the contribution of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation by pioglitazone in the regulation of the inflammatory response and L. braziliensis killing by monocytes. Pioglitazone is an oral drug used in the treatment of diabetes, and its main mechanism of action is through the activation of PPAR-γ, which is expressed in many cell types of the immune response. We found that activation of PPAR-γ by pioglitazone decreases the inflammatory response in CL patients without affecting L. braziliensis killing by monocytes. Our data suggest that pioglitazone may serve as an adjunctive treatment for CL caused by L. braziliensis.

show abstract

Short-chain fatty acids ameliorate necrotizing enterocolitis-like intestinal injury through enhancing Notch1-mediated single immunoglobulin interleukin-1-related receptor, toll-interacting protein, and A20 induction

Venkatraman

Menden

et al. 2023

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR), toll interacting protein (TOLLIP) and A20 are major inhibitors of Toll Like Receptor (TLR) signaling induced postnatally in the neonatal intestine. Short chain fatty acids (SCFAs), fermentation products of indigestible carbohydrates produced by symbiotic bacteria, inhibit intestinal inflammation. Herein, we investigated the mechanisms by which SCFAs regulate SIGIRR, A20, and TOLLIP expression and mitigate experimental necrotizing enterocolitis (NEC). Butyrate induced NOTCH activation by repressing sirtuin 1 (SIRT1)-mediated deacetylation of the Notch intracellular domain (NICD) in human intestinal epithelial cells (HIEC). Overexpression of NICD induced SIGIRR, A20, and TOLLIP expression. Chromatin immunoprecipitation revealed that butyrate-induced NICD binds to the SIGIRR, A20, and TOLLIP gene promoters. Notch1-shRNA suppressed butyrate-induced SIGIRR/A20 upregulation in mouse enteroids and HIEC. Flagellin (TLR5 agonist)-induced inflammation in HIEC was inhibited by butyrate in a SIGIRR-dependent manner. Neonatal mice fed butyrate had increased NICD, A20, SIGIRR, and TOLLIP expression in the ileal epithelium. Butyrate inhibited experimental NEC-induced intestinal apoptosis, cytokine expression and histological injury. Our data suggest that SCFAs can regulate expression of the major negative regulators of TLR signaling in the neonatal intestine through Notch1 and ameliorate experimental NEC. Enteral SCFAs supplementation in preterm infants provides a promising bacteria-free, therapeutic option for NEC.

show abstract

Inhibition of gamma-secretase activity without interfering in Notch signalling decreases inflammatory response in patients with cutaneous leishmaniasis

Abstract: Inhibition of Gamma-secretase activity without interfering in Notch signaling decreases inflammatory response in patients with cutaneous leishmaniasis, Emerging Microbes & Infections,

Cited by 3 publications

References 38 publications

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Downregulates the Inflammatory Response in Cutaneous Leishmaniasis Patients Without Interfering in Leishmania braziliensis Killing by Monocytes

Short-chain fatty acids ameliorate necrotizing enterocolitis-like intestinal injury through enhancing Notch1-mediated single immunoglobulin interleukin-1-related receptor, toll-interacting protein, and A20 induction

Contact Info

Product

Resources

About