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Development and Functional Characterization of Murine Tolerogenic Dendritic Cells
Published on: May 18, 2018
IL-10 production from dendritic cells is associated with DC SIGN in human leprosy
Sudhir Kumar1, Raza Ali Naqvi, Ajaz A Bhat
1Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.
Insights
Defective antigen presenting cells (APCs) in leprosy influence disease severity. Mycobacterium leprae component triggers DC SIGN on dendritic cells (DCs), increasing IL-10 production via NF-κB signaling, driving disease progression towards the lepromatous pole.
Area of Science:
- Immunology
- Cell Biology
- Infectious Diseases
Background:
- Antigen presenting cells (APCs) play a crucial role in modulating host immune responses and disease severity in leprosy.
- The functional state of APCs, particularly dendritic cells (DCs), and their signaling pathways are implicated in the spectrum of leprosy, from tuberculoid (BT/TT) to lepromatous (BL/LL) forms.
Purpose of the Study:
- To investigate the phenotypic characteristics of APCs in leprosy patients.
- To determine the influence of DC SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin) on Interleukin-10 (IL-10) production during the progression of leprosy.
- To elucidate the role of Mycobacterium leprae components in modulating DC function and immune signaling.
Main Methods:
- Phenotypic analysis of APCs, including CD11c+ cells and CD83 expression, in leprosy patients.
- In vitro treatment of dendritic cells (DCs) with cytokines (GM-CSF, IL-4) and Mycobacterium leprae component (ManLAM).
- Assessment of nuclear translocation and acetylation of NF-κB, IL-10 production, and T cell proliferation following anti-DC SIGN treatment.
Main Results:
- Increased DC SIGN expression was observed on CD11c+ cells from BL/LL leprosy patients, alongside an impaired form of CD83.
- Treatment with ManLAM induced increased nuclear presence of NF-κB and elevated IL-10 production in DCs, suggesting DC SIGN's role in promoting the BL/LL phenotype.
- Anti-DC SIGN treatment inhibited NF-κB nuclear translocation and acetylation, leading to reduced IL-10 production and enhanced T cell proliferation.
Conclusions:
- Mycobacterium leprae components activate DC SIGN on DCs, which promotes IL-10 production through NF-κB signaling.
- This modulation of intracellular signaling pathways drives the immune response towards the lepromatous pole in leprosy pathogenesis.
- Targeting DC SIGN may offer a therapeutic strategy to restore immune balance in leprosy.
Abstract:
The defective antigen presenting ability of antigen presenting cells (APCs) modulates host cytokines and co-stimulatory signals that may lead to severity of leprosy. In the present study, we sought to evaluate the phenotypic features of APCs along with whether DC SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin) influences IL-10 production while moving from tuberculoid (BT/TT) to lepromatous (BL/LL) pole in leprosy pathogenesis. The study revealed an increased expression of DC SIGN on CD11c⁺ cells from BL/LL patients and an impaired form of CD83 (∼50 kDa). However, the cells after treatment with GM-CSF+IL-4+ManLAM showed an increased expression of similar form of CD83 on DCs. Upon treatment with ManLAM, DCs were found to show increased nuclear presence of NF-κB, thus leading to higher IL-10 production. High IL-10 production from ManLAM treated PBMCs further suggested the role of DC SIGN in subverting the DCs function towards BL/LL pole of leprosy. Anti-DC SIGN treatment resulting in restricted nuclear ingression of NF-κB as well as its acetylation along with enhanced T cell proliferation validated our findings. In conclusion, Mycobacterium leprae component triggers DC SIGN on DCs to induce production of IL-10 by modulating intracellular signalling pathway at the level of transcription factor NF-κB towards BL/LL pole of disease.
