Skin Disease In Mice Research Articles

CD169+ Skin Macrophages Function as a Specialized Subpopulation in Promoting Psoriasis-like Skin Disease in Mice.

Skin macrophages are critical to maintain and restore skin homeostasis. They serve as major producers of cytokines and chemokines in the skin, participating in diverse biological processes such as wound healing and psoriasis. The heterogeneity and functional diversity of macrophage subpopulations endow them with multifaceted roles in psoriasis development. A distinct subpopulation of skin macrophages, characterized by high expression of CD169, has been reported to exist in both mouse and human skin. However, its role in psoriasis remains unknown. Here, we report that CD169+ macrophages exhibit increased abundance in imiquimod (IMQ) induced psoriasis-like skin lesions. Specific depletion of CD169+ macrophages in CD169-ditheria toxin receptor (CD169-DTR) mice inhibits IMQ-induced psoriasis, resulting in milder symptoms, diminished proinflammatory cytokine levels and reduced proportion of Th17 cells within the skin lesions. Furthermore, transcriptomic analysis uncovers enhanced activity in CD169+ macrophages when compared with CD169- macrophages, characterized by upregulated genes that are associated with cell activation and cell metabolism. Mechanistically, CD169+ macrophages isolated from IMQ-induced skin lesions produce more proinflammatory cytokines and exhibit enhanced ability to promote Th17 cell differentiation in vitro. Collectively, our findings highlight the crucial involvement of CD169+ macrophages in psoriasis development and offer novel insights into the heterogeneity of skin macrophages in the context of psoriasis.

Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus-Like Inflammation.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.

Effects of Dietary Protein Intake on Cutaneous and Systemic Inflammation in Mice with Acute Experimental Psoriasis.

Background: Psoriasis is a systemic inflammatory disorder, primarily characterized by skin plaques. It is linked to co-morbidities including cardiovascular disease and metabolic syndrome. Several studies demonstrate that dietary habits can influence psoriasis development and severity. However, the effect of different dietary protein levels on psoriasis development and severity is poorly understood. In this study, we examine the influence of dietary protein on psoriasis-like skin disease in mice. Methods: We fed male C57BL/6J mice with regular, low protein and high protein chow for 4 weeks. Afterwards, we induced psoriasis-like skin disease by topical imiquimod (IMQ)-treatment on ear and back skin. The local cutaneous and systemic inflammatory response was investigated using flow cytometry analysis, histology and quantitative rt-PCR. Results: After 5 days of IMQ-treatment, both diets reduced bodyweight in mice, whereas only the high protein diet slightly aggravated IMQ-induced skin inflammation. IMQ-treatment induced infiltration of myeloid cells, neutrophils, and monocytes/macrophages into skin and spleen independently of diet. After IMQ-treatment, circulating neutrophils and reactive oxygen species were increased in mice on low and high protein diets. Conclusion: Different dietary protein levels had no striking effect on IMQ-induced psoriasis but aggravated the systemic pro-inflammatory phenotype.

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells.

Psoriasis is an autoimmune and inflammatory skin disease affecting around 2–3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8+CD44highCD62Llow effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4+Foxp3+ Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4+CD25− T cells into CD4+Foxp3+ Tregs in vitro. Interestingly, depleting CD4+Foxp3+ Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4+Foxp3+ Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-γ, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKα and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic.

Correction: PAMs ameliorates the imiquimod-induced psoriasis-like skin disease in mice by inhibition of translocation of NF-κB and production of inflammatory cytokines.

[This corrects the article DOI: 10.1371/journal.pone.0176823.].

Regulation of IL-22BP in psoriasis

IL-22 is a potent pro-inflammatory cytokine upregulated in psoriasis and in other inflammatory diseases. The function of IL-22 is regulated by the soluble scavenging receptor, IL-22 binding protein (IL-22BP or IL-22RA2). However, the role and regulation of IL-22BP itself in the pathogenesis of inflammatory disease remain unclear. We used the TLR7 agonist Imiquimod (IMQ) to induce a psoriasis-like skin disease in mice and found a strong downregulation of IL-22BP in the affected skin as well as in the lymph nodes of animals treated with IMQ. We also analysed psoriatic skin of patients and compared this to skin of healthy donors. Interestingly, IL-22BP expression was similarly downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. Since IL-22BP is expressed foremost in dendritic cells, we characterized its expression in monocyte-derived dendritic cells (MoDC) during maturation. In this way, we found Prostaglandin E2 (PGE2) to be a potent suppressor of IL-22BP expression in vitro. We conclude that regulation of IL-22BP by inflammatory mediators is an important step for the progression of inflammation in the skin and possibly also in other autoimmune diseases.

PAMs ameliorates the imiquimod-induced psoriasis-like skin disease in mice by inhibition of translocation of NF-κB and production of inflammatory cytokines.

Psoriasis is a chronic and persistent inflammatory skin disease seriously affecting the quality of human life. In this study, we reported an ancient formula of Chinese folk medicine, the natural plant antimicrobial solution (PAMs) for its anti-inflammatory effects and proposed the primary mechanisms on inhibiting the inflammatory response in TNF-α/IFN-γ-induced HaCaT cells and imiquimod-induced psoriasis-like skin disease mouse model. Two main functional components of hydroxysafflor Yellow A and allantoin in PAMs were quantified by HPLC to be 94.2±2.2 and 262.9±12.5 μg/mL respectively. PAMs could significantly reduce the gene expression and inflammatory cytokines production of Macrophage-Derived Chemokine (MDC), IL-8 and IL-6 in TNF-α/IFN-γ-induced HaCaT cells. PAMs also significantly ameliorates the psoriatic-like symptoms in a mouse model with the evaluation scores for both the single (scales, thickness, erythema) and cumulative features were in the order of blank control < Dexamethasone < PAMs < 50% ethanol < model groups. The results were further confirmed by hematoxylin-eosin staining, RT-qPCR and immunohistochemistry. The down-regulated gene expression of IL-8, TNF-α, ICAM-1 and IL-23 in mouse tissues was consistent with the results from those of the HaCaT cells. The inhibition of psoriasis-like skin inflammation by PAMs was correlated with the inactivation of the translocation of P65 protein into cellular nucleus, indicating the inhibition of the inflammatory NF-κB signaling pathway. Taken together, these findings suggest that PAMs may be a promising drug candidate for the treatment of inflammatory skin disorders, such as psoriasis.

RIG‐I antiviral signaling drives interleukin‐23 production and psoriasis‐like skin disease

Retinoic acid inducible‐gene I (RIG‐I) functions as one of the major sensors of RNA viruses. DDX58, which encodes the RIG‐I protein, has been newly identified as a susceptibility gene in psoriasis. Here, we show that the activation of RIG‐I by 5′ppp‐dsRNA, its synthetic ligand, directly causes the production of IL‐23 and triggers psoriasis‐like skin disease in mice. Repeated injections of IL‐23 to the ears failed to induce IL‐23 production and a full psoriasis‐like skin phenotype, in either germ‐free or RIG‐I‐deficient mice. RIG‐I is also critical for a full development of skin inflammation in imiquimod (IMQ)‐induced psoriasis‐like mouse model. Furthermore, RIG‐I‐mediated endogenous IL‐23 production was mainly confined to the CD11c+ dendritic cells (DCs) via nuclear factor‐kappa B (NF‐κB) signaling, and stimulated RIG‐I expression in an auto‐regulatory feedback loop. Thus, our data suggest that the dysregulation in the antiviral immune responses of hosts through the innate pattern recognition receptors may trigger the skin inflammatory conditions in the pathophysiology of psoriasis.

Deficiency of IκB Kinase β in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), peripherally developed myelin-reactive T lymphocytes stimulate myeloid cells (ie, microglia and infiltrated macrophages) to trigger an inflammatory reaction in the central nervous system, resulting in demyelination and neurodegeneration. IκB kinase β (IKKβ) is a kinase that modulates transcription of inflammatory genes. To investigate the pathogenic role of IKKβ in MS, we developed strains in which IKKβ was conditionally ablated in myeloid cells and established active or passive EAE in these animals. Deficiency of IKKβ in myeloid cells ameliorated EAE symptoms and suppressed neuroinflammation, as shown by decreased infiltration of T lymphocytes and macrophages and reduced inflammatory gene transcription in the spinal cord at the peak or end stage of EAE. Myeloid deficiency of IKKβ also reduced the transcription of Rorc or Il17 genes in T lymphocytes isolated from lymph nodes, spleen, and spinal cord of EAE mice. Moreover, cultured splenocytes isolated from myeloid IKKβ-deficient EAE mice released less IL-17, interferon-γ, and granulocyte-macrophage colony-stimulating factor after treatment with myelin peptide than splenocytes from IKKβ wild-type EAE mice. Thus, deficiency of myeloid IKKβ attenuates the severity of EAE by inhibiting both the neuroinflammatory activity and the activation of encephalitogenic T lymphocytes. These results suggest IKKβ may be a potential target for MS patients, especially when neuroinflammation is the primary problem.

Comparative Effects of Bee Venom and Clindamycin on Propionibacterium acnes-induced Inflammatory Skin Disease in Mice

Acne is the most common skin disease, causing significant psychosocial problems for those afflicted. Currently, available agents for acne treatment have limited to use with antibiotics, which cause side effects or resistance. Bee venom (BV) has traditionally been used as a treatment for a wide variety of ailments such as inflammatory diseases. Despite its well documented antiinflammatory property, it has not been fully demonstrated regarding the influence of BV against inflammatory acne. This study evaluated the anti-inflammatory property of BV and clindamycin, which is well-known antibiotics against acne treatment. To induce inflammation in vivo using Propionibactierium acnes (P. acnes), 1×10 7 CFU of living P. acnes were intradermally injected into the ear of mice. BV (50, 100, 200 and 400μg/g) in gel and clindamycin (1%) was applied epicutaneously on the ear. Epicutaneous administration of BV or clindamycin decreased the number of infiltrated inflammatory cells and inflammatory cytokines in the ear, thereby relieving P. acnes-induced ear swelling and subsequent proinflammatory cytokine expression, especially at the dose of 200μg/g of BV. The anti-inflammatory effects of BV is relatively same or superior compared to those of clindamycin in P. acnes-induced inflammation in vivo. These results demonstrate that the potential of using BV as an alternative treatment to the antibiotic therapy of acne.

Immunodeficiency and disseminated mycobacterial infection associated with homozygous nonsense mutation of IKKβ

A, Genealogical tree for the kindred. Arrow highlights index case. Asterisks denote family members who died within the first 2 months of life with febrile illnesses. B, Histology showing granuloma in skin by hematoxylin and eosin staining.

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

A8.25 CARD9 mediates autoantibody-induced autoimmune diseases by linking the SYK tyrosine kinase to CHEMOKINE production

Background and ObjectivesCARD9 is a CARMA-like intracellular protein that is highly expressed in innate immune cells. In contrast to its well-defined role in fungal recognition pathways in dendritic cells, its...

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c(+) DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin(+) DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin(neg) DCs in vivo. In conclusion, TLR7-activated Langerin(neg) cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

Effects of Phosphorylation of Herpes Simplex Virus 1 Envelope Glycoprotein B by Us3 Kinase In Vivo and In Vitro

We recently reported that the herpes simplex virus 1 (HSV-1) Us3 protein kinase phosphorylates threonine at position 887 (Thr-887) in the cytoplasmic tail of envelope glycoprotein B (gB) (A. Kato, J. Arii, I. Shiratori, H. Akashi, H. Arase, and Y. Kawaguchi, J. Virol. 83:250-261, 2009; T. Wisner, C. C. Wright, A. Kato, Y. Kawaguchi, F. Mou, J. D. Baines, R. J. Roller and D. C. Johnson, J. Virol. 83:3115-3126, 2009). In the studies reported here, we examined the effect(s) of this phosphorylation on viral replication and pathogenesis in vivo and present data showing that replacement of gB Thr-887 by alanine significantly reduced viral replication in the mouse cornea and development of herpes stroma keratitis and periocular skin disease in mice. The same effects have been reported for mice infected with a recombinant HSV-1 carrying a kinase-inactive mutant of Us3. These observations suggested that Us3 phosphorylation of gB Thr-887 played a critical role in viral replication in vivo and in HSV-1 pathogenesis. In addition, we generated a monoclonal antibody that specifically reacted with phosphorylated gB Thr-887 and used this antibody to show that Us3 phosphorylation of gB Thr-887 regulated subcellular localization of gB, particularly on the cell surface of infected cells.

Loss of SOCS7 in mice results in severe cutaneous disease and increased mast cell activation

The Suppressor of Cytokine Signaling (SOCS) protein family plays a central role in the negative regulation of cytokine action and has been implicated in the development of atopic diseases. Lack of SOCS7 is associated with severe skin disease in mice. We sought to explore the underlying mechanisms resulting in this phenotype. Skin samples were analyzed and serum immunoglobulin production was measured. Cytokine production by bone marrow derived mast cells was determined by ELISA. Mast cell thymic stromal lymphopoietin (TSLP) production was assessed by quantitative real-time PCR. Data obtained revealed that Socs7(-/-) mice have increased serum IgE and IgG(1) production and exhibit an increased mast cell infiltrate, as well as un-provoked mast cell degranulation in the dermis as compared to controls. In vitro, bone marrow derived mast cells from Socs7(-/-) mice are hyperactive to IgE-mediated stimuli, with elevated production of pro-inflammatory cytokines (IL-13, IL-6, TNF-alpha). Further, activated Socs7(-/-) bone marrow derived mast cells have increased IL-7Ralpha transcript, which is part of the heterodimeric receptor for TSLP. Finally, lack of SOCS7 was accompanied by an increase in TSLP mRNA and protein production by mast cells following FcepsilonRI aggregation. These data implicate SOCS7 in the modulation of allergic inflammation and demonstrate that SOCS7 is involved in the regulation of TSLP signaling in mast cells.

Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice

The transcription factor serum response factor (SRF) plays a crucial role in the development of several organs. However, its role in the skin has not been explored. Here, we show that keratinocytes in normal human and mouse skin expressed high levels of SRF but that SRF expression was strongly downregulated in the hyperproliferative epidermis of wounded and psoriatic skin. Keratinocyte-specific deletion within the mouse SRF locus during embryonic development caused edema and skin blistering, and all animals died in utero. Postnatal loss of mouse SRF in keratinocytes resulted in the development of psoriasis-like skin lesions. These lesions were characterized by inflammation, hyperproliferation, and abnormal differentiation of keratinocytes as well as by disruption of the actin cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-cell and cell-matrix contacts and loss of cell compaction in all epidermal layers. siRNA-mediated knockdown of SRF in primary human keratinocytes revealed that the cytoskeletal abnormalities and adhesion defects were a direct consequence of the loss of SRF. In contrast, the hyperproliferation observed in vivo was an indirect effect that was most likely a consequence of the inflammation. These results reveal that loss of SRF disrupts epidermal homeostasis and strongly suggest its involvement in the pathogenesis of hyperproliferative skin diseases, including psoriasis.

Regulation of the Catalytic Activity of Herpes Simplex Virus 1 Protein Kinase Us3 by Autophosphorylation and Its Role in Pathogenesis

Us3 is a serine/threonine protein kinase encoded by herpes simplex virus 1 (HSV-1). We recently identified serine at Us3 position 147 (Ser-147) as a physiological phosphorylation site of Us3 (A. Kato, M. Tanaka, M. Yamamoto, R. Asai, T. Sata, Y. Nishiyama, and Y. Kawaguchi, J. Virol. 82:6172-6189, 2008). In the present study, we investigated the effects of phosphorylation of Us3 Ser-147 on regulation of Us3 catalytic activity in infected cells and on HSV-1 pathogenesis. Our results were as follows. (i) Only a small fraction of Us3 purified from infected cells was phosphorylated at Ser-147. (ii) Us3 phosphorylated at Ser-147 purified from infected cells had significantly higher kinase activity than Us3 not phosphorylated at Ser-147. (iii) Phosphorylation of Us3 Ser-147 in infected cells was dependent on Us3 kinase activity. (iv) Replacement of Us3 Ser-147 by alanine significantly reduced viral replication in the mouse cornea and the development of herpes stromal keratitis and periocular skin disease in mice. These results indicated that Us3 catalytic activity is tightly regulated by autophosphorylation of Ser-147 in infected cells and that regulation of Us3 activity by autophosphorylation appeared to play a critical role in viral replication in vivo and in HSV-1 pathogenesis.

The Pathophysiology of Bullous Pemphigoid

Bullous pemphigoid (BP) is a blistering skin disease characterized by an autoimmune response to 2 hemidesmosomal proteins within the dermal-epidermal junction, designated BP180 and BP230. While BP230 localizes intracellularly and associates with the hemidesmosomal plaque, BP180 is a transmembrane glycoprotein with an extracellular domain. Most BP patients have autoantibodies binding to an immunodominant region of BP180, the noncollagenous 16A domain (NC16A), which is located extracellularly close to the transmembrane domain of the protein. Autoreactive T and B cell responses to BP180 have been found in patients with BP. Passive transfer of antibodies to the murine BP180 ectodomain triggers a blistering skin disease in mice that closely mimics human BP. Lesion formation in this animal model depends upon complement activation, mast cell degranulation and accumulation of neutrophils and eosinophils. Patients' autoantibodies to BP180 induce dermal-epidermal separation in cryosections of human skin when co-incubated with leukocytes. The loss of cell-matrix adhesion is mediated by proteinases released by granulocytes. The increased knowledge of the pathophysiology of BP should facilitate the development of novel therapeutic strategies for this disease.

TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2.

The I kappa B kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKK gamma) regulatory subunit, phosphorylates I kappa B proteins, targeting them for degradation and thus inducing activation of NF-kappa B (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-kappa B activation through pro-inflammatory signals. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-kappa B. Previous studies suggested that NF-kappa B has a function in the growth regulation of epidermal keratinocytes. Mice lacking RelB or I kappa B alpha, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions. However, the function of NF-kappa B in the epidermis remains unclear. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-kappa B activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumour necrosis factor-mediated, alpha beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-kappa B activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.