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Dexamethasone selectively inhibits differentiation of cord blood stem cell derived-dendritic cell (DC) precursors
1Department of Pediatrics, Virginia Commonwealth University Health System, 401 North 12th Street, Room 6-500, Richmond, VA 23298, USA. emainali@hsc.vcu.edu
Insights
Perinatal dexamethasone exposure disrupts immune cell development. It specifically harms developing dendritic cells (DCs), increasing apoptosis and hindering their ability to stimulate T cells.
Area of Science:
- Immunology
- Developmental Biology
- Pharmacology
Background:
- Perinatal dexamethasone exposure can negatively impact the immune system, leading to increased susceptibility to infections and developmental issues.
- Dendritic cells (DCs), crucial immune cells, are particularly sensitive to dexamethasone (Dx) effects.
- Cord blood CD34+-derived DCs are a key focus for understanding these impacts.
Purpose of the Study:
- To investigate the specific effects of dexamethasone (Dx) on distinct developmental stages of cord blood CD34+-derived dendritic cells (DCs).
- To determine the impact of Dx on glucocorticoid receptor (GcR) translocation, apoptosis, differentiation, and function of developing DCs.
Main Methods:
- Cord blood CD34+ cells were differentiated into DCs through distinct stages: pre-DC, immature, and mature.
- Dexamethasone (Dx) was added at different developmental time points.
- Effects on precursor number, GcR translocation, apoptosis, cell surface marker expression (CD1a, CD86, CD83), endocytic activity, cytokine secretion (IL-6, IL-10), and T cell stimulation were analyzed.
Main Results:
- Dx exposure during pre-DC to immature DC differentiation triggered GcR nuclear translocation and enhanced DC apoptosis.
- This exposure suppressed CD1a+ cell differentiation, inhibited CD86 and CD83 expression, and reduced T cell stimulation.
- Dx also suppressed IL-6 secretion while enhancing IL-10 secretion, maintaining DC endocytic activity.
- Dx added during the maturation stage had less pronounced effects.
Conclusions:
- Dexamethasone (Dx) significantly impacts dendritic cell (DC) development, primarily during the differentiation of pre-DCs into immature DCs.
- Dx stalls DC maturation and selectively induces apoptosis, with peak sensitivity observed during this critical differentiation phase.
- These findings highlight the vulnerability of developing immune cells to perinatal dexamethasone exposure and its potential long-term consequences.
Abstract:
Perinatal dexamethasone (Dx) alters the immune system leading to increased infections and developmental abnormalities. Dendritic cells (DCs) derived from cord-blood monocytes are especially Dx sensitive and we sought to determine the effects of Dx on cord-blood CD34+-DCs. Distinct stages of cord-blood CD34+-DC development were delineated: pre-DC, immature, and mature DCs. Dx added during development of pre-DCs did not suppress precursor number, or translocate the glucocorticoid receptor (GcR) from the cytoplasm to the nucleus. However, Dx added during pre-DCs differentiation into immature DCs, prompted GcR translocation to the nucleus, enhanced DC apoptosis, suppressed differentiation to CD1a+ cells, inhibited expression of CD86, reduced subsequent CD83 expression, maintained DC endocytic activity, suppressed IL-6 secretion, enhanced IL-10 secretion, and reduced DC-mediated T cell stimulation. Dx added during the maturation stage caused less dramatic effects. Thus, Dx stalled maturation, selectively induced apoptosis of developing DCs and the sensitivity peaked during pre-DCs differentiation into immature DCs.
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