Dermal CD14 + Dendritic Cell and Macrophage Infection by Dengue Virus Is Stimulated by Interleukin-4

Abstract

Dengue virus (DENV) is responsible for the most prevalent arthropod-borne viral infection in humans. Events decisive for disease development occur in the skin after virus inoculation by the mosquito. Yet, the role of human dermis-resident immune cells in dengue infection and disease remains elusive. Here we investigated how dermal dendritic cells (dDCs) and macrophages (dMs) react to DENV and impact on immunopathology. We show that both CD1c(+) and CD14(+) dDC subsets were infected, but viral load greatly increased in CD14(+) dDCs upon IL-4 stimulation, which correlated with upregulation of virus-binding lectins Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN/CD209) and mannose receptor (CD206). IL-4 also enhanced T-cell activation by dDCs, which was further increased upon dengue infection. dMs purified from digested dermis were initially poorly infected but actively replicated the virus and produced TNF-α upon lectin upregulation in response to IL-4. DC-SIGN(+) cells are abundant in inflammatory skin with scabies infection or Th2-type dermatitis, suggesting that skin reactions to mosquito bites heighten the risk of infection and subsequent immunopathology. Our data identify dDCs and dMs as primary arbovirus target cells in humans and suggest that dDCs initiate a potent virus-directed T-cell response, whereas dMs fuel the inflammatory cascade characteristic of dengue fever.

The Correlation of CD206, CD209, and Disease Severity in Behçet’s Disease with Arthritis

“…CD206 was highly expressed with significance in active BD patients with cutaneous symptoms (49.7 ± 35.2%) compared to inactive BD patients (4.7 ± 3.1%) ( p = 0.007) and HCs (7.4 ± 0.8%) ( p = 0.02). It is known that CD206 facilitates viral infections such as Dengue virus [28], hepatitis B virus [29], lymphadenopathy associated virus [30], and human immunodeficiency virus [31]. In collagen induced arthritis, CD206 was seen in the inflamed joints by micro-computed tomography imaging [32].…”

Early dengue virus interactions: the role of dendritic cells during infection

“…DENV infection on DCs resident in human dermis was also evaluated. Schaeffer and colleagues showed that the CD1c + and CD14 + dermal DC subsets, as well as dermal macrophages, are the primary cell targets for DENV, but the viral load increased in the CD14 + dermal DCs after stimulation with IL-4 (Schaeffer et al, 2015).…”

Immune responses to dengue virus in the skin

“…Interestingly CD141 + DCs, which make up a minority population in the skin, were not observed to be infected [21]. Macrophages and CD1c + and CD14 + dermal DCs that are matured with IL-4 have also been shown to be more susceptible to DENV infection, potentially due to the upregulation of DENV receptors, DC-specific ICAM3-grabbing non-integrin (DC-SIGN) and the mannose receptor, in response to the cytokine treatment [22]. In spite of being infection targets, monocyte/macrophage lineage cells could play a dual role in infection since it has been shown that depletion of macrophages leads to early reduced infection in lymph nodes, yet to later increased infection burden in vivo systemically [23].…”