Administration of substance P during a primary immune response amplifies the secondary immune response via a long-lasting effect on CD8+ T lymphocytes

Abstract

Atopic dermatitis can be exacerbated or induced by scratching or psychological stress; both cause the release of substance P (SP) from sensory nerves. Therefore, SP may have an etiological role in mechanisms underlying AD. Here, we show that administration of SP during the primary immune response (PIR) imprinted long-lasting pro-inflammatory immunity, resulting in exacerbation of the secondary immune response (SIR) in the absence of further SP. Five days after sensitization with dinitrofluorobenzene (DNFB), challenge with DNFB together with SP ("SP-Group") resulted in an increased PIR (as evaluated by ear swelling and granulocyte infiltration) compared to DNFB only ("Control-Group"). On day 26, after inflammation completely subsided, a second challenge with DNFB only (without SP) caused an increased SIR in the "SP-Group" compared to controls. Pretreatment on day 5 with spantide, an SP receptor antagonist, prevented increased ear swelling in the "SP-Group" not only on day 5 (PIR) but also on day 26 (SIR). In contrast, spantide treatment on day 26 did not affect the SIR. Adoptive transfer experiments suggested that CD8(+) T cells were involved in mediating enhanced SIR in animals pretreated on day 5 with SP. The present study offers a novel experimental approach to an uninvestigated facet of the pro-inflammatory effect of SP, i.e., exacerbation of inflammation via a long-term and indirect influence on CD8(+) T lymphocytes.

Up-regulated expression of substance P in CD8+ T cells and NK1R on monocytes of atopic dermatitis

“…Based on the current observation that up-regulated expression of SP in CD8 + T cells of AD, we believe that CD8 + T cells are more likely a causative cell type in the development of AD. A study that demonstrates a proinflammatory effect of SP on exacerbation of inflammation via long-term and indirect action on CD8 + T lymphocytes may support our hypothesis [32]. …”

Neuropeptide substance P and the immune response

“…They also showed that the other members of the tachykinin family, neurokinins A and B, had no effect on the differentiation of naive and memory T cells (Cunin et al, 2011). Finally, administration of substance P during the primary immune response amplifies the secondary immune response by activating CD8+ T lymphocytes (Ikeda et al, 2007). …”

The immunomodulatory effects of tachykinins and their receptors

“…Recently, Zhang et al 70 found that SP and CD8 + T cells (cytotoxic T cells that secrete an array of pro‐inflammatory cytokines) are likely to have a role in the pathogenesis of atopic dermatitis through releasing SP. In line with this, Ikeda et al 71 showed that SP leads to exacerbation of inflammation via a long‐term and indirect effect on CD8 + T lymphocytes. Interestingly, intravenous injection of SP increased the levels of IL‐4, IL‐6, and IL‐10 in the lesion site of the spinal cord injury 72 .…”