Roles for IL-1 and TNFα in dynamic behavioral responses of Langerhans cells to topical hapten application

Abstract

Background-To understand the behavioral biology of Langerhans cells (LCs), we recently recorded time-lapse images of LCs in the knock-in mice expressing the I-Aβ chain tagged with the enhanced green fluorescence protein (EGFP). EGFP + LCs showed relatively limited motility in the steady state, whereas topical application of dinitrofluorobenzene (DNFB) markedly augmented a unique movement of dendrites characterized by rhythmic extension and retraction, termed dSEARCH, and triggered amoeba-like lateral migration of cell bodies. Objective-To define underlying mechanisms by which hapten treatment alters LC behaviors.Methods-The I-Aβ-EGFP mice received subcutaneous (s.c.) injection of recombinant IL-1α or TNFα (50 ng/animal) and dynamic behaviors of EGFP + LCs were recorded by time-lapse confocal microscopy at several time points to measure their dSEARCH activities and lateral migration. In a different sset of experiments, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor-2 (sTNFR2) (0.5 μg/animal) was s.c. injected into the ear skin 30 minutes before topical application of DNFB, and LC behaviors analyzed thirty hours later.Results-Local injection of IL-1α or TNFα induced significant, albeit modest, augmentation of both dSEARCH and lateral migration. Co-injection of TNFα and IL-1α further exacerbated motile activities in a synergistic manner by similar magnitudes observed after DNFB application. Conversely, DNFB-induced behavioral changes were inhibited completely by local injection of IL-1Ra or sTNFR2.Conclusion-IL-1 and TNFα serve as equally important mediators of hapten-induced alteration of LC behaviors. Motile activities of epidermal LCs are reprogrammed by selected cytokines known to be produced by keratinocytes under pathological conditions.

External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers

“…TNF and IL-1 have been reported to be KC-derived proinflammatory cytokines rapidly induced by tape stripping (Wood et al, 1992) and leading to LC activation and dSEARCH motion (Enk et al, 1993;Nishibu et al, 2007). As expected, subcutaneous injection of TNF or IL-1, but not PBS, induced numerous clusters of MHC II high LCs within 12 h (Fig.…”

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

“…LCs, positioned covertly under the TJs, are polarized to send their dendrites outside of the TJ barrier when activated by danger signals such as TSLP, TNF-α, and IL-1β, presumably secreted from keratinocytes that somehow detect SC damages (Figure 2 and refs. 47,[53][54][55][56]. The SG1 layer allows LCs to sample for foreign materials that have violated the SC barrier (13).…”

“…After SC barrier abrogation, protease-active allergens and uncontrolled intrinsic proteases, as well as bacterial molecules such as lipoteichoic acid of gram-positive bacteria, might agonize Par2 and TLRs on keratinocytes, respectively (7,55,112,123). Keratinocytes then produce TNF-α, IL-1, and thymic stromal lymphopoietin (TSLP) (47,55), in response to which LCs become activated (54,56,124). Alternatively, protease-active allergens might directly obscure the TJ barrier and then penetrate the epidermis (7), where they directly or indirectly activate LCs.…”

Herpes Simplex Virus Infects Skin γδ T Cells before Langerhans Cells and Impedes Migration of Infected Langerhans Cells by Inducing Apoptosis and Blocking E-Cadherin Downregulation

“…IL-1b and TNF-a have been shown to enhance LC migration from the epithelium of mice and induce E-cadherin downregulation (37)(38)(39). Given that HSV was observed to block LC E-cadherin downregulation, we next investigated whether this was associated with impaired skin cytokine production.…”