Controlling the Allergic Reaction

Science Signaling  22 Jan 2013:
Vol. 6, Issue 259, pp. ec21
DOI: 10.1126/scisignal.2003984

The allergic reaction in skin cells is regulated by the adaptive immune response, in which allergen-specific T lymphocytes (T cells) are activated by mature antigen-presenting dendritic cells (DCs). Hypersensitive reactions can cause allergic contact dermatitis (ACD). Alarmins are proteins that function as endogenous danger signals that amplify the immune response through various receptors, including Toll-like receptors (TLRs). The alarmins Mrp8 and Mrp14, functioning individually or as the heteromeric complex Mrp8/14, stimulate the immune response through TLR-4 and can promote autoimmune diseases, such as arthritis and lupus. Petersen et al. showed that, in addition to their stimulatory role, Mrp8 and Mrp14 also have an inhibitory role in adaptive immunity. Although incubation with purified Mrp8 or the Mrp8/14 complex activated bone marrow–derived DCs (BMDCs) from wild-type mice and induced T cell proliferation in a TLR-4–dependent manner in vitro, Mrp14–/– mice (which also lacked Mrp8 on the protein level) exhibited more severe phenotypes of ACD than did wild-type mice. This hypersensitivity was due to increased differentiation of BMDCs and, subsequently, activation of T cells. Bone marrow progenitor cells from wild-type mice pretreated with Mrp8 showed decreased lipolysaccharide (LPS)–induced differentiation, which was dependent on TLR-4. In contrast, BMDCs from Mrp14–/– mice showed increased endogenous and LPS-induced maturation. Wild-type–derived T cells, cocultured with LPS-activated BMDCs from Mrp14–/– mice exhibited increased proliferation compared with the proliferation of those cocultured with activated BMDCs from wild-type mice. Additionally, time-lapse video microscopy of 3D cell cultures showed that LPS-activated BMDCs from Mrp14–/– mice formed more contacts with and activated more T cells than those from wild-type mice. To elicit ACD in vivo, 2,4-dinitrofluorobenzene (DNFB) was applied to the skin of the mice. DNFB increased the serum concentration of Mrp8/14 in wild-type mice, and DCs from their Mrp14–/– counterparts showed increased proinflammatory cytokine secretion and T cell proliferation. Therefore, by inhibiting early differentiation of DC progenitors, the Mrp8/14 complex suppresses the adaptive inflammatory response to allergens. Thus, the alarmins Mrp8 and Mrp14 both stimulate and limit the immune response, by activating mature DCs and inhibiting the differentiation of DC progenitors, respectively.

B. Petersen, M. Wolf, J. Austermann, P. van Lent, D. Foell, M. Ahlmann, V. Kupas, K. Loser, C. Sorg, J. Roth, T. Vogl, The alarmin Mrp8/14 as regulator of the adaptive immune response during allergic contact dermatitis. EMBO J. 32, 100–111 (2013). [PubMed]