CXCR4 signaling controls dendritic cell location and activation at steady-state and in inflammation

Blood ◽  
2021 ◽  
Author(s):  
Carmen Gallego ◽  
Mathias Vétillard ◽  
Joseph Calmette ◽  
Mélanie Roriz ◽  
Viviana Marin-Esteban ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Immune Responses ◽  
Chemokine Receptors ◽  
High Susceptibility ◽  
Cxcr4 Signaling ◽  
Whim Syndrome ◽  
Plasmacytoid Dcs ◽  
And Function ◽  
Specific Contribution

Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans-cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology.

scholarly journals Congenital Deficiency of Conventional Dendritic Cells Promotes the Development of Atopic Dermatitis-Like Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yotaro Nishikawa ◽  
Tomohiro Fukaya ◽  
Takehito Fukui ◽  
Tomofumi Uto ◽  
Hideaki Takagi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Atopic Dermatitis ◽  
Immune Responses ◽  
Skin Barrier ◽  
Lymphoid Cells ◽  
Congenital Deficiency ◽  
T Cell Immune Responses ◽  
Group 2 ◽  
And Function ◽  
The Impact

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of Thelper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Here, we describe the impact of the constitutive loss of cDCs on the progression of AD-like inflammation by using binary transgenic (Tg) mice that constitutively lacked CD11chi cDCs. Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of Staphylococcus aureus (S. aureus), that associated with disease flare. Thus, cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.

Turnover of Dermal Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2283-2283
Author(s):  
Milena Bogunovic ◽  
Florent Ginhoux ◽  
Martine Loubeau ◽  
Miriam Merad
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Chemokine Receptors ◽  
Uv Light ◽  
Small Population ◽  
Specific Marker ◽  
Chimeric Mice ◽  
Complete Replacement ◽  
Surface Marker Expression ◽  
High Level

Abstract We have previously shown that in steady state conditions, epidermal Langerhans cells (LCs) derive from a radio-resistant precursor that self-renew in the skin throughout life (Merad et al. 2002). In the current study we addressed the mechanisms that regulate the turnover of other subsets of skin antigen presenting cells (APCs). Based on cell surface marker expression, we characterized two populations of APCs in the mice dermis including CD11c+ CD11b+ cells and CD11b+ CD11c- cells (likely corresponding to dermal dendritic cells (DDCs) and macrophages respectively). To explore the turnover of DDCs we reconstituted lethally irradiated CD45.2+ C57BL/6 mice with bone marrow (BM) cells isolated from CD45.1+ C57BL/6 congenic mice and followed the replacement of host DDCs by donor DDCs. Interestingly, we found that despite 95% blood and BM chimerism, 20% of CD11c+ DDCs remained of host (CD45.2+) origin for at least 1 year after transplant, while 80% of DDCs and dermal macrophages appeared to be of donor (CD45.1+) origin as early as at 4 weeks after transplant. The radio-resistant CD11c+ cells homogenously expressed CD11b, F4/80, high-level MHC II and the co-stimulatory molecules CD40 and CD86, while only 10% of them expressed the LC specific marker (langerin) suggesting that these cells represent migrating LCs. To explore whether radio-resistant DDCs are able to proliferate locally, we administered bromodeoxyuridine (BrdU) to (CD45.1+ BM > CD45.2+ recipient) chimeric mice, 8 weeks after transplant. Because at the time of BrdU administration, blood cells in chimeric mice were of donor origin, incorporation of BrdU in host DDCs should reflect local proliferation. Indeed, we found that 30% of host DDCs incorporate BrdU after two weeks of BrdU labeling suggesting that radio-resistant DDCs proliferate in situ. In contrast to steady state conditions, exposure of chimeric mice to ultraviolet (UV) light led to complete replacement of the remaining host DDCs by circulating donor DDCs. To explore the nature of the chemokines playing a role in the recruitment of circulating DDCs to inflamed skin, we reconstituted lethally irradiated CD45.1+ mice with a 1:1 mixture of CD45.1+ autologous BM cells and CD45.2+ BM cells deficient in the chemokine receptors CCR2 or CCR6. Two weeks after transplant, we exposed the mice to UV light and followed the recruitment of mutant and wild type DDCs in the skin. Importantly, we found that 3 weeks after UV exposure, the % of CD45.2+ CCR2−/− DDCs was 8 fold lower than CD45.1+ CCR2+/+ DDCs, while there was no difference between the % of CCR6−/− and CCR6+/+ DDCs. These results suggest that the recruitment of donor DDCs is dependent on the chemokine receptor CCR2 but not CCR6, while CCR2 and CCR6 were required for the recruitment of circulating LC precursors. Taken together, our results suggest that, similar to LCs, a small population of DDCs is radio-resistant and proliferate in quiescent skin. Whether this subset of DDCs represents a local precursor for epidermal LCs will be the subject of further studies.

Ontogeny and innate properties of neonatal dendritic cells

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 585-591 ◽  
Author(s):  
Cheng-Ming Sun ◽  
Laurence Fiette ◽  
Myriam Tanguy ◽  
Claude Leclerc ◽  
Richard Lo-Man
Keyword(s):  
Dendritic Cells ◽  
Early Life ◽  
Innate Immune ◽  
Type I ◽  
Adult Size ◽  
Immune Functions ◽  
High Susceptibility ◽  
Major Histocompatibility Complexes ◽  
Plasmacytoid Dcs

Abstract We investigated whether a developmental immaturity of the dendritic cells (DCs) compartment could contribute to the high susceptibility to infections observed in newborns. DCs are among the first cells to colonize the spleen, but the ontogeny of DC subsets follows distinct steps. At birth, plasmacytoid DCs and CD4-CD8α- DCs are found in the spleen, whereas CD8α+ and CD4+ DCs are not present. Then, the CD8α+ DC compartment quickly develops and reaches an adult size by day 7, whereas the CD4+ DC compartment slowly increases to become predominant by the age of 3 weeks. The production of interleukin (IL)–12p70 by DCs is particularly efficient after birth, reflecting the stronger capacity of the neonatal CD8α- DCs to secrete IL-12 compared with its adult counterpart. Like-wise, neonatal DCs produced type I and II interferons. In vivo, following microbial stimulation, up-regulation of major histocompatibility complexes (MHCs) and of costimulatory molecules on DCs was induced clearly showing the activation of neonatal DCs in the neonatal environment. Therefore, despite a markedly different DC subset composition in early life compared with the adult DC compartment, neonatal DCs are fully competent in their innate immune functions.

scholarly journals SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues

2021 ◽  
Vol 22 (17) ◽  
pp. 9228
Author(s):  
Guoshuai Cai ◽  
Mulong Du ◽  
Yohan Bossé ◽  
Helmut Albrecht ◽  
Fei Qin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Single Cell ◽  
Upper Airway ◽  
Innate Immune ◽  
Healthy Controls ◽  
Innate Immune Responses ◽  
Current Spreading ◽  
Plasmacytoid Dcs

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.

scholarly journals Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

2015 ◽  
Vol 112 (13) ◽  
pp. 4044-4049 ◽  
Author(s):  
Emma M. Carrington ◽  
Jian-Guo Zhang ◽  
Robyn M. Sutherland ◽  
Ingela B. Vikstrom ◽  
Jamie L. Brady ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Survival ◽  
Molecular Basis ◽  
Family Members ◽  
Specific Inhibitor ◽  
Immune Intervention ◽  
Molecular Control ◽  
Plasmacytoid Dcs

Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and their dependence on individual antiapoptotic BCL-2 family members. Compared with cDCs, pDCs had higher expression of BCL-2, lower A1, and similar levels of MCL-1 and BCL-XL. Transgenic overexpression of BCL-2 increased the pDC pool size in vivo with only minor impact on cDCs. With a view to immune intervention, we tested BCL-2 inhibitors and found that ABT-199 (the BCL-2 specific inhibitor) selectively killed pDCs but not cDCs. Conversely, genetic knockdown of A1 profoundly reduced the proportion of cDCs but not pDCs. We also found that conditional ablation of MCL-1 significantly reduced the size of both DC populations in mice and impeded DC-mediated immune responses. Thus, we revealed that the two DC types have different cell survival requirements. The molecular basis of survival of different DC subsets thus advocates the antagonism of selective BCL-2 family members for treating diseases pertaining to distinct DC subsets.

scholarly journals Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

2013 ◽  
Vol 210 (8) ◽  
pp. 1635-1646 ◽  
Author(s):  
Alberto Pinzon-Charry ◽  
Tonia Woodberry ◽  
Vivian Kienzle ◽  
Virginia McPhun ◽  
Gabriela Minigo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Acute Infection ◽  
Plasmodium Infection ◽  
Spontaneous Apoptosis ◽  
Cross Sectional ◽  
And Function ◽  
Immature Cells

Malaria causes significant morbidity worldwide and a vaccine is urgently required. Plasmodium infection causes considerable immune dysregulation, and elicitation of vaccine immunity remains challenging. Given the central role of dendritic cells (DCs) in initiating immunity, understanding their biology during malaria will improve vaccination outcomes. Circulating DCs are particularly important, as they shape immune responses in vivo and reflect the functional status of other subpopulations. We performed cross-sectional and longitudinal assessments of the frequency, phenotype, and function of circulating DC in 67 Papuan adults during acute uncomplicated P. falciparum, P. vivax, and convalescent P. falciparum infections. We demonstrate that malaria patients display a significant reduction in circulating DC numbers and the concurrent accumulation of immature cells. Such alteration is associated with marked levels of spontaneous apoptosis and impairment in the ability of DC to mature, capture, and present antigens to T cells. Interestingly, sustained levels of plasma IL-10 were observed in patients with acute infection and were implicated in the induction of DC apoptosis. DC apoptosis was reversed upon IL-10 blockade, and DC function recovered when IL-10 levels returned to baseline by convalescence. Our data provide key information on the mechanisms behind DC suppression during malaria and will assist in developing strategies to better harness DC’s immunotherapeutic potential.

scholarly journals The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting

2013 ◽  
Vol 31 (1) ◽  
pp. 563-604 ◽  
Author(s):  
Miriam Merad ◽  
Priyanka Sathe ◽  
Julie Helft ◽  
Jennifer Miller ◽  
Arthur Mortha
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Dendritic Cell ◽  
Cell Lineage ◽  
And Function

scholarly journals The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Reza Hosseini ◽  
Leila Asef-Kabiri ◽  
Hassan Yousefi ◽  
Hamzeh Sarvnaz ◽  
Majid Salehi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Treatment Options ◽  
Vaccination Strategy ◽  
Therapeutic Approaches ◽  
Therapeutic Level ◽  
Tumor Exosomes ◽  
And Function ◽  
Insight Into ◽  
Dominant Influence

AbstractTumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide future treatment options, in particular DC-based vaccination strategy, and review advances in the design and discovery of exosome inhibitors. Understanding the exosomal content and the pathways by which TDEs are responsible for immune evasion may help to revise treatment rationales and devise novel therapeutic approaches to overcome the hurdles in cancer treatment.

Dendritic Cells as Arbiters of Peritoneal Immune Responses

2006 ◽  
Vol 26 (1) ◽  
pp. 8-25 ◽  
Author(s):  
Michelle L. McCully ◽  
Joaquín Madrenas
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Immune Defense ◽  
Dendritic Cell Differentiation ◽  
Adaptive Immune ◽  
The Past ◽  
Key Players ◽  
And Function

During the past few years, there has been a substantial increase in the understanding of innate immunity. Dendritic cells are emerging as key players in the orchestration of this early phase of immune responses, with a role that will translate into the subsequent type of adaptive immune response against infection. Here we provide an overview of dendritic cell differentiation and function, with particular emphasis on those features unique to the immune defense of the peritoneal cavity and in the context of peritoneal dialysis-associated immune responses. The reader is referred to the primary references included in the accompanying list for specific details in this fascinating field.

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