Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice.

Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.

Adaptive immune response to model antigens is impaired in murine leukocyte-adhesion deficiency-1 revealing elevated activation thresholds in vivo.

Absence of ß2 integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary immunodeficiency syndrome. Although extensive in vitro work has established an essential function of ß2 integrins in adhesive and signaling properties for cells of the innate and adaptive immune system, their respective participation in an altered adaptive immunity in LAD1 patients are complex and only partly understood in vivo. Therefore, we investigated adaptive immune responses towards different T-dependent antigens in a murine LAD1 model of ß2 integrin-deficiency (CD18⁻/⁻). CD18⁻/⁻ mice generated only weak IgG responses after immunization with tetanus toxoid (TT). In contrast, robust hapten- and protein-specific immune responses were observed after immunization with highly haptenated antigens such as (4-hydroxy-3-nitrophenyl)21 acetyl chicken γ globulin (NP21-CG), even though regularly structured germinal centers with specificity for the defined antigens/haptens in CD18⁻/⁻ mice remained absent. However, a decrease in the hapten/protein ratio lowered the efficacy of immune responses in CD18⁻/⁻ mice, whereas a mere reduction of the antigen dose was less crucial. Importantly, haptenation of TT with NP (NP-TT) efficiently restored a robust IgG response also to TT. Our findings may stimulate further studies on a modification of vaccination strategies using highly haptenated antigens in individuals suffering from LAD1.

Protection from autoimmune brain inflammation in mice lacking IFN-regulatory factor-1 is associated with Th2-type cytokines.

IFN-regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of IFN-induced genes and type I IFN. It has previously been demonstrated that IRF-1-deficient mice show reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by a peptide from myelin basic protein. To further study the role of IRF-1 in brain inflammation, we analyzed EAE induced by immunization with a myelin oligodendrocyte glycoprotein-derived peptide in 129/Sv mice lacking IRF-1. We found that these mice were almost completely resistant to EAE induction and that this unresponsiveness was intrinsically related to the IRF-1 deficiency of the T cells, but not with any other cell type. Furthermore, we show that the amelioration of EAE was associated with increased production of T(h)2-type and decreased production of T(h)1-type cytokines. These results demonstrate that absence of IRF-1 in myelin-specific T cells results in protection from severe EAE and is associated with a skewing of the T cell response towards T(h)2.