PPARγ modulated inflammatory response of human dendritic cell subsets to engulfed apoptotic neutrophils

Abstract

The means of how phagocytes handle apoptotic cells has a great impact on the outcome of immune responses. Here, we show that phagocytosis of allogeneic, apoptotic neutrophils by human monocyte-derived DCs is slow and less efficient than that of macrophages, and CD1a(-) DCs are more active in the engulfment of apoptotic neutrophils than CD1a(+) DCs. Blocking DC-SIGN function partially interferes with the uptake of apoptotic cells, and long-term interaction of apoptotic neutrophils with DCs makes them prone to proinflammatory cytokine responses. Engulfment of apoptotic cells sensitizes CD1a(-) DCs for high IL-8, TNF-α, IL-6, and CD1a(+) cells for IL-12 and IL-10 cytokine secretion elicited by additional inflammatory stimuli, which also result in the polarization of autologous T lymphocytes to Th1 effector cells. Ligand-induced activation of PPARγ by RSG results in enhanced phagocytosis, but the proinflammatory response and the capacity to trigger Th1 cell activation of CD1a(-) DCs are not enhanced. These results demonstrate that DCs are able to respond to allogeneic, apoptotic neutrophils with inflammatory cytokines and T cell responses in a subtype-specific manner that is modulated by the anti-inflammatory effects of PPARγ.

The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response

“…The concomitant pro-or anti-inflammatory stimuli [25,26] and the site of antigen encounter [27,28] determine the extent and direction of DC-induced T cell stimulation. According to our recent results, human monocyte-derived DCs, in contrast to macrophages, can respond to allogeneic apoptotic neutrophils with a robust, inflammatory response and T lymphocyte activation [29].…”

“…When human monocyte-derived iDCs, isolated from buffy coats and differentiated in vitro for 5 days, were exposed to apoptotic neutrophils, it was found that they could also engulf apoptotic neutrophils [29]. iDCs were less effective than macrophages; even after several hours of coincubation, the percentage of DCs with engulfed apoptotic cells was 9 -25% varying among donors.…”

“…It was shown previously that monocyte-derived human DCs activated by LPS and IFN-␥ respond to allogeneic apoptotic neutrophils with inflammatory cytokine production, and the engulfment of apoptotic neutrophils leads to the activation of T cells [29]. To test the effects of Dex on DC-mediated inflammatory responses, we differentiated monocytes to iDCs in the presence or absence of Dex and then loaded the cells with allogeneic apoptotic neutrophils.…”

“…However, the effect of GCs on the phagocytosis of apoptotic cells by DCs has not been investigated. Furthermore, knowing from our previous results [29] that long-term interaction of apoptotic neutrophils with DCs renders them prone to proinflammatory cytokine responses and based on reports in the literature that GCs induce a tolerogenic phenotype of DCs, we found it important to investigate whether Dex can suppress the proinflammatory effect of apoptotic neutrophils. According to the presented results, Dex increased the capacity of iDCs to engulf apoptotic cells through up-regulation of several apoptophagocytic genes.…”

Glycobiology of cell death: when glycans and lectins govern cell fate

“…It is worth noting that APCs engulfing apoptotic cells can secrete soluble mediators and cytokines capable of activating or blunting adaptive immune responses. 118,122 Thus, silent clearance of 'unwanted-self' or 'dangerous' immune cells, via lectin-glycan interactions, represents an evolutionarily conserved homeostatic mechanisms to reduce or prevent exuberant inflammatory responses.…”