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• W2056531852 abstract "For most people that experience allergic contact hypersensitivity (CHS) reactions, for instance exposure to poison ivy, the result is usually itchy rashes and blisters. However, for others, such reactions can be severe. They are usually brought on by repeated contact with an irritant or chemical hapten that triggers pre-sensitized immune cells to create an inflammatory environment at the contact site. These inflammatory events are characterized by the infiltration of hapten-specific T lymphocytes and the production of pro-inflammatory cytokines such as IL1β, IL6 and kerantinocyte-derived chemokine CXCL1. Although much evidence exists for how these responses are mediated at the cellular level, the molecular signals that drive such responses are still unclear. In this edition of Immunology and Cell Biology, Ledford et al.1 describe a exciting new role for the small protein Onzin in eliciting inflammatory CHS immune responses. Onzin is an evolutionarily conserved, 112 amino acid, cysteine-rich protein that is abundantly expressed in a range of tissues and immune cells and was first described as a LIF regulated gene in the mouse endometrium2 and as placental-enriched gene 8 (Plac8) by microarray analysis.3 Although very little is known about this mysterious protein, more recently, Onzin has been linked to myeloid cell differentiation, proliferation and survival.4,5,6 The authors took their lead from earlier results showing that onzin was dramatically upregulated in the lymph nodes of mice draining chemically sensitized skin.7 Using Onzin-deficient mice and combinations of bone marrow irradiation chimeras they then systematically showed that Onzin expression by bone marrow-derived cells was required for normal contact sensitivity to chemical haptens. Dampened CHS in Onzin-deficient mice correlated with a specific defect in the production of two of the major inflammatory factors, IL6 and CXCL1 at the challenge site. Interestingly, Onzin-deficiency in bone marrow-derived cells did not appear to affect the initial immune priming stage (also known as the sensitization phase) as the adoptive transfer of sensitized Onzin-deficient lymphocytes into naïve animals was able to mediate rapid CHS, at levels comparable to wild-type (measured by ear swelling in the rechallenge site). Conversely, transfer of sensitized wild-type lymphocytes into Onzin-deficient naïve recipients resulted in a strong reduction in CHS. These results exclude a cell intrinsic defect in conventional T-cell responses and point towards the contribution of another bone marrow-derived cell present at the rechallenge site that requires Onzin to modulate the CHS response (refer to Figure 1). One cell type that fits the bill are the infiltrating neutrophils, because previously this same group had shown that the expression of Onzin is important for neutrophil effector function.8 However, depletion of neutrophils with anti-Gr1 antibodies showed no alterations to CHS, thus excluding a role for these cells and most likely the Gr1high inflammatory monocytes. So which cell type(s) require Onzin to promote CHS? As skin-resident Langerhans cells are radio-resistant, the bone-marrow irradiation chimera excluded the possibility of these cells mediating the observed affects. Dermal-resident macrophages or DC such as those that express CD11b or CD103 could possibly depend on Onzin for functionality. But perhaps the most likely candidates are myeloid cells that rapidly infiltrate tissues and produce inflammatory products. One such example is the plasmacytoid DCs that express high levels of Onzin.9 Also a role for infiltrating mast cells, basophils or eosinophils, which are all known to secrete IL6, was also not excluded by the authors. One could envisage a scenario where Onzin is involved in the regulation of myeloid cell differentiation and production of cytokines such as IL6, which in turn influences hapten-specific T lymphocytes and keratinocytes to promote strong CHS (Figure 1). Intriguingly, how Onzin functions at the molecular level is still unclear. But perhaps a recent study can shed some light on this issue. This study showed that Onzin can directly interact via its cysteine-rich domain with the transcription factor C/EBPβ to regulate adipose tissue formation.10 Coincidently, previous work has shown that C/EBPβ drives the expression of the il6 gene in mouse myeloid cells.11 Taken together, one could speculate that Onzin, via direct interaction with C/EBPβ, may activate the expression of the il6 gene. Interestingly, Onzin has also been found in association with another important ‘master regulator’ of myeloid cell differentiation and function PU.1.4 Only time will tell whether Onzin does indeed function in this way and if it directly interacts with chromatin and other transcription factors to regulate myeloid cell differentiation and function. Nevertheless, this simple yet elegant study by Ledford et al.1 has shown us that this small, yet significant protein deserves further investigation into both its regulation and function. (a) In the sensitization phase there is normal migration of hapten-carrying dendritic cells from sensitized skin and T-cell activation in draining lymph nodes in the presence and absence of Onzin. (b) In the elicitation phase hapten-specific T cells infiltrate into rechallenged skin and receive pro-inflammatory signals (such as IL6) from myeloid cells with the result being strong CHS (left panel). However, in the absence of Onzin, the production of IL6 and CXCL1 is low, resulting in less hapten-specific T cell infiltration and more mild CHS (right panel)." @default.
• W2056531852 created "2016-06-24" @default.
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• W2056531852 date "2012-01-24" @default.
• W2056531852 modified "2023-09-26" @default.
• W2056531852 title "From little things big things grow: a new role for onzin in contact hypersensitivity responses" @default.
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• W2056531852 doi "https://doi.org/10.1038/icb.2011.116" @default.
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