Long-Term Exposure to Inflammation Induces Differential Cytokine Patterns and Apoptosis in Dendritic Cells

Abstract

The activation of dendritic cells (DCs) has profound implications and governs the control of adaptive immunity. However, long-term activation might drive exhaustion of immune cells and negatively affect functionality. Here, long-term vs. short-term exposure to bacterial lipopolysaccharide and interferon (IFN)γ was evaluated on human monocyte-derived DCs. Long-term activated DC1s began to undergo apoptosis concomitant with a profound TAM-receptor and efferocytosis-dependent induction of interleukin (IL)-10. Whereas, levels of IL-12p70 and IL-10 were positively correlated upon short-term activation, an inverse association occured upon long-term activation and, while short-term activated CD1a+ DCs were main producers of IL-12p70, CD1a− DCs were the main fraction that underwent apoptosis and released IL-10 upon long-term activation. Moreover, pre-apoptotic long-term activated DCs were no longer able to activate alloreactive IFNγ-responsive T cells present in peripheral blood mononuclear cells from healthy volunteers. The IFNγ response was mediated by IL-12p70, as a strong reduction in IFNγ was observed following blockade with an IL-12p70 neutralizing antibody. Finally, multiplex analysis of DC supernatants revealed a particular pattern of proteins associated with apoptosis, cancer and chronic inflammation partly overlapping with gold standard DCs well-known for their inability to secrete IL-12p70. In conclusion, long-term activated DC1s significantly changed their profile toward a non-functional, tumor-promoting and anti-inflammatory phenotype.

Fascin inhibitor increases intratumoral dendritic cell activation and anti-cancer immunity

“…However, there is a strong correlation between this subset of DCs and the exhausted CD8 + T cell and Treg cell signature within the TME, implying that this subset of intratumoral DCs might be related to T cell dysfunction, despite their maturation features ( Zhang et al, 2019 ). Moreover, the ability to expand antigen-specific CD8 + T cells is a feature of specialized effector DCs at early stages of maturation, and it is suppressed in exhausted DCs at late stages of maturation and in DCs matured under the conditions of chronic inflammation ( Abdi et al, 2012 ; Carstensen et al, 2019 ; Rodrigue-Gervais et al, 2010 ). Long-term activation of DCs under conditions of chronic inflammation and cancer impairs their functionality, and a lack of IL-12 secretion results in non-functional T cells devoid of IFN-γ ( Carstensen et al, 2019 ).…”

“…Moreover, the ability to expand antigen-specific CD8 + T cells is a feature of specialized effector DCs at early stages of maturation, and it is suppressed in exhausted DCs at late stages of maturation and in DCs matured under the conditions of chronic inflammation ( Abdi et al, 2012 ; Carstensen et al, 2019 ; Rodrigue-Gervais et al, 2010 ). Long-term activation of DCs under conditions of chronic inflammation and cancer impairs their functionality, and a lack of IL-12 secretion results in non-functional T cells devoid of IFN-γ ( Carstensen et al, 2019 ). Fascin inhibition, IL-4 inhibition, and CD40 activation, together with anti-PD-1 antibody, could release the inhibition and re-activate these DCs ( Garris et al, 2018 ; Maier et al, 2020 ; this study).…”

Redox Regulation of the Immune Response: Nitro-Oxidative Stress and Antioxidants Regulate Macrophage, Neutrophil, and T and B Lymphocyte, and Dendritic and Natural Killer Cell Functions

“…Direct effects include damage to functional macromolecules and increased activation of apoptotic pathways (199,200). Indirect effects include increased Wnt signalling (90), epigenetic dysregulation and compromised TLR activity (201)(202)(203).…”

Efferocytosis and Its Associated Cytokines: A Light on Non-tumor and Tumor Diseases?

“…103,104 IFN also functions in tumors, showing an anti-tumor role of IFN-g. Long-term-activated DCs fail to effectively activate alloreactive IFN-g-responsive T cells, and they changed their profile toward a non-functional and tumor-promoting phenotype. 105 In addition, in the last step of efferocytosis, Cunha et al 106 showed that tumor-associated macrophages with LC3-associated phagocytosis (LAP) displayed M2 characteristics and reduced secretion of IFN-g, which suppressed the anti-tumor response. TAM lacking LAP exhibited M1 characteristics and increased stimulator of IFN genes (STING)dependent type I IFN production to promote IFN-g, resulting in anti-tumor responses.…”