Exposure to Ionizing Radiation Induces the Migration of Cutaneous Dendritic Cells by a CCR7-Dependent Mechanism

Abstract

In the event of a deliberate or accidental radiological emergency, the skin would likely receive substantial ionizing radiation (IR) poisoning which could negatively impact cellular proliferation, communication, and immune-regulation within the cutaneous microenvironment. Indeed, as we have previously shown, local IR exposure to the murine ear causes a reduction of two types of cutaneous dendritic cells (cDC), including interstitial DC (iDC) of the dermis and Langerhans cells (LC) of the epidermis, in a dose and time dependent manner. These APCs are critical regulators of skin homeostasis, immuno-surveillance, and the induction of T and B cell-mediated immunity as previously demonstrated using conditional cDC knockout mice. To mimic a radiological emergency, we developed a murine model of sub-lethal total body irradiation (TBI). Our data would suggest that TBI results in the reduction of cDC from the murine ear that was not due to a systemic response to IR as a loss was not observed in shielded ears. We further determined that this reduction was due, in part, to the up-regulation of the chemoattractant CCL21 on lymphatic vessels as well as CCR7 expressed on cDC. Migration as a potential mechanism was confirmed using CCR7−/− mice where cDC were not depleted following TBI. Finally, we demonstrated that the loss of cDC following TBI results in an impaired contact hypersensitivity (CHS) response to hapten by using a modified CHS protocol. Taken together, these data suggest that IR exposure may result in diminished immuno-surveillance in the skin, which could render the host more susceptible to pathogens.

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease

“…Further myeloablative conditioning by total body irradiation (TBI) before transplantation and anti-thymocyte globulin (ATG) prophylaxis against aGvHD may interact with and modulate the effect of subsequent photochemotherapy. Ionizing irradiation is known to damage DNA and to alter the dendritic cell populations of the skin - effects shared with photochemotherapy [11,12,13]. ATG is generally decreasing both the host dendritic cell population, which is a target for donor cell-mediated immunity, and the donor dendritic cell population, which is a director of donor T-cell tropism [14].…”

VEGF-C/VEGFR-3 Signaling Regulates Chemokine Gradients and Lymphocyte Migration From Tissues to Lymphatics.

“…Overexpression of CCL21 impairs cellular retention leading to an attenuated immune response. Indeed, upregulation of CCL21 prior to hapten challenge promotes CCR7 + cells egress from the skin leading to impaired CHS responses (67). Our data indicated that down-regulation of CCL21 could be reversed by HPSE blockade or PI3K activation, which were down-stream of VEGFR-3 signaling.…”

Whole Body Irradiation Induces Cutaneous Dendritic Cells Depletion via NF-κB Activation

“…It was reported that local irradiation triggered migration of LC in epidermal in a time and dose dependent manner [6]. Recently Cummings et al [2] found that sub-lethal irradiation induced cutaneous DC migration to the draining LN. In this study our data showed that WBI caused a depletion of cDC in epidermal and dermal.…”

“…Recently, Ryan et al found that sub-lethal irradiation induced cDC migration from skin to the draining LN [2], while our department had found that ionizing radiation inhibited the migration capacity of DC in vitro [7]. Furthermore, as occupational exposure is becoming a major part of the radiation exposure, the migration capacity of cDC after moderate dose of whole body irradiation (WBI) is drawing more and more attention.…”

“…Both LC and dDC steadily migrates from the skin to the draining lymph node in a low rate [2]. And the migration is greatly enhanced by antigen or other inflammatory stimuli, which ensures an effective initiation of adaptive immune response [3].…”