Skin samples were obtained at P7 from K14-Cre-IKK2. Ten fields per mouse were counted. Sections in the upper panels are stained H&E. In mice, epidermis-specific deletion of inhibitor of NF-κB (IκB) kinase 2 (IKK2) results in a skin phenotype that mimics human psoriasis in several aspects. Schön, M.P., Detmar, M., Parker, C.M. HHS Interestingly, these cells showed positive staining for CD83, an Ig-like adhesion receptor that is present on the surface of monocyte-derived dendritic cells but is already synthesized in monocytes/macrophages (27). Nickoloff, B.J., Wrone-Smith, T. 1999. In this review, we summarize the recent findings on TRMs in mouse and zebrafish and compare the similarity/differences between these two species. Origin and treatment of mice. All other reagents were purchased from Sigma-Aldrich unless indicated otherwise. Phosphatidylcholine (LIPOID E PC) was obtained from Lipoid. Figure 1. IL-12 is produced by macrophages and can stimulate the production of IFN-γ in an autocrine fashion (42); IL- 23 is known to be produced by keratinocytes in psoriatic lesions (43, 44) and can directly activate macrophages (45). Elimination of skin macrophages by subcutaneous injection of clodronate liposomes was accompanied by inhibition of granulocyte migration into the skin and resulted in a dramatic attenuation of psoriasis-like skin changes. Scale bar: 40 μm. Histochemical chloracetate esterase staining revealed that homozygous, but not heterozygous, deletion of CD18 resulted in the absence of granulocytes from the skin of the affected mice (Figure 5, B and C). Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. Lowes, M.A., et al.  |  C and D show unspecific staining of sebaceous glands due to the use of streptavidin-coupled fluorochrome for detection of biotinylated primary antibodies. in: In situ localization of CD83-positive dendritic cells in psoriatic lesions. Our results demonstrate that in mice epidermal keratinocytes can initiate a hyperproliferative, inflammatory, IFN-gamma-independent, psoriasis-like skin disease whose development requires essential contributions from skin macrophages but not from granulocytes or alphabeta T lymphocytes. White dotted lines indicate the position of the epidermal basement membrane. With respect to the role of TNF in macrophage activation it is interesting that in TNFR-I–deficient transgenic mice expressing the IκBα super-repressor in the epidermis, selective reconstitution of TNFR-I–positive bone marrow–derived cells was not sufficient to recreate the inflammatory-hyperproliferative phenotype (38). TAMs express immune checkpoint modulators [e.g., B7 family, B7-homolog family including programmed death ligand 1 (PD-L1)] (3) that directly suppress activated T cells. (L and M) F4/80-positive epithelium-lining macrophages in a developing lesion at P4 (L) and in a fully developed lesion at P7 (M). Thepen, T., et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. | Respective markers are stained green; nuclei are stained red. Methods: Xenogeneic rat skin grafts were transplanted to macrophage colony, stimulating factor (M-CSF)/macrophage-deficient osteopetrotic ([OP]-/-) and wild-type control mice. Since elimination of skin macrophages prevented both the accumulation of granulocytes and T cells and the development of the psoriasis-like skin condition, it was unclear whether the improvement of the skin disease was a direct consequence of macrophage depletion or the result of inhibited granulocyte and T cell migration or expansion. Reference information: J. Clin. Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis. | 2009 Oct 1;183(7):4755-63. doi: 10.4049/jimmunol.0900521. Inflammatory and immune cell function in psoriasis: II. Lee, E., et al. Elimination of granulocytes from the skin of K14-Cre-IKK2fl/fl Figure 4. To analyze the composition of the inflammatory cell infiltrate, we stained skin sections with antibodies against different immune cell markers. Characterization of lymphocyte-dependent angiogenesis using a SCID mouse: human skin model of psoriasis. 2009 May;41(5):963-8. doi: 10.1016/j.biocel.2008.10.022. 2003. Massive mobilization of granulocytes from the bone marrow was demonstrated by our results of white blood cell counting: there was an elevated number of circulating granulocytes with a relative increase in stab cells (deviation to the left) in K14-Cre-IKK2fl/fl mice compared with controls (Figure 5A). Mast cell numbers were as follows (no. Mice deficient for CD18 have been reported previously to be defective for granulocyte migration into areas of organ inflammation (23). 2019 Jul 28;8(8):785. doi: 10.3390/cells8080785. Scharffetter-Kochanek, K., et al. Nuclei are stained red. 1997. Tumor necrosis factor receptor 1- mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Psoriasis is a common skin disease, the pathogenesis of which has not yet been resolved. Analysis of gene expression in the skin of K14-Cre-IKK2fl/fl mice and control mice was performed in collaboration with the service laboratory of the Interdisciplinary Center for Clinical Research, Westfaelische Wilhelms–Universitaet Muenster (Muenster, Germany). Histopathological investigation at P7 revealed that the skin changes observed in huTNFR:Fc-treated K14-Cre-IKK2fl/fl mice were much less pronounced than those in untreated K14-Cre-IKK2fl/fl mice or in K14-Cre-IKK2fl/fl mice treated with human IgG: the skin was thinner, its structure was close to normal, in most areas K14 expression was confined to the basal epidermal layer, K10 and loricrin were present in the epidermis, and the invasion of inflammatory cells into the skin was suppressed (Figure 1). On their surfaces, granulocytes express different isoforms of CD11 and CD18, which form heterodimeric adhesion receptors that mediate these adhesive contacts. In order to identify mechanisms relevant to the pathogenesis of the observed inflammatory skin disease, we set out to investigate the pathogenic roles of inflammatory cells and mediators. As controls we injected 7 K14-Cre-IKK2fl/fl mice with PBS-containing liposomes (control liposomes). Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, Becher B. J Clin Invest. Misbehaving macrophages in the pathogenesis of psoriasis. Markur, D. JCI PubMed Light microscopic images of paraffin-embedded skin sections (top 3 panels) and confocal images of cryostat skin sections (bottom 6 panels) from control mice and K14-Cre-IKK2fl/fl mice with clodronate or control liposomes injected as indicated. RNA was extracted from snap-frozen skin of newborn K14-Cre-IKK2fl/fl mice and control mice using Tri Does anyone know the surface markers and any gene that are specific to Lung and skin macrophage (human and mouse)? 2012 Jun;122(6):2252-6. doi: 10.1172/JCI61862. One of the most important immune cells involved in wound healing is the macrophage, which exhibits different immunological functions in the skin, including phagocytosis and antigen-presentation. Weber-Matthiesen, K., Sterry, W. 1990. Schon, M.P., Boehncke, W.H. Ward NL, Loyd CM, Wolfram JA, Diaconu D, Michaels CM, McCormick TS. In mice, epidermis-specific deletion of inhibitor of NF-κB (IκB) kinase 2 (IKK2) results in a skin phenotype that mimics human psoriasis in several aspects. 2001. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. Please enable it to take advantage of the complete set of features! the mouse analogue of CD14), indicating the existence of a pool of dermal MACs that is established prenatally and persists in adulthood, independently from circulating monocytes [ 10, 42, 43 ], showing that MACs are indeed … Attenuation of the skin phenotype after injection of clodronate liposomes demonstrated that in our mice, macrophages were necessary for the psoriasis-like skin disease to develop. In order to evaluate the significance of our findings for humans, other models of psoriasis will have to be considered. It has been shown that dermal T cells, neutrophils, mast cells, and Langerhans cells are not depleted by clodronate liposome treatment (22). Wang, H., et al. | We therefore carried out gene expression analysis in the skin of K14-Cre-IKK2fl/fl mice and control mice at P2 and P3, prior to macroscopically or histologically detectable skin changes. Elimination of granulocytes from the skin of K14-Cre-IKK2 fl/fl mice does not suppress…, Figure 8. JCI Improvement of the psoriasis-like skin phenotype after injection of clodronate liposomes. Histological analysis. This would provide a possible explanation for the great heterogeneity of psoriasis patients regarding their treatment susceptibility. 2009). Mice were backcrossed to the C57BL/6 genetic background for at least 5 generations. 2020 Jul 2;21(13):4733. doi: 10.3390/ijms21134733. doi:10.1172/JCI27179. The failure to respond to IFN-γ receptor deletion indicates that in our setting TNF is more important than IFN-γ for the induction of skin inflammation. Targeted deletion of the receptor for IFN-gamma revealed that the pathogenesis of the skin disease does not depend on classical IFN-gamma-mediated macrophage activation. We have recently described the phenotype of mice with keratinocyte-specific deletion of inhibitor of NF-κB (IκB) kinase 2 (IKK2; a component of the IκB kinase complex that is required for NF-κB activation by proinflammatory signals), which were homozygous for a floxed (fl) IKK2 allele and expressed Cre recombinase under the control of the keratin 14 (K14) promoter (K14-Cre-IKK2fl/fl mice) (18). Van Rooijen, N. 1989. Pathogenic function of IL-1 beta in psoriasiform skin lesions of flaky skin (fsn/fsn) mice. Psoriasis is a common skin disease, the pathogenesis of which has not yet been resolved. Skin phenotypes that met these criteria were consequently termed psoriasis or psoriasiform or psoriasis-like skin disease (reviewed in ref. Version Miura, H., Sano, S., Higashiyama, M., Yoshikawa, K., Itami, S. 2000. Lung and skin macrophage markers (human and mouse)? The major populations of the skin cells included macrophages, dendritic cells and fibroblasts. They play critical roles in homeostasis and host defense in each tissue. Robert, C., Kupper, T.S. TNF and the pathology of the skin. Wang H, Peters T, Sindrilaru A, Scharffetter-Kochanek K. J Invest Dermatol. Trepicchio, W.L., Dorner, A.J. We carried out immunostainings for differentiation specific markers in order to analyze the degree of disturbance of terminal keratinocyte differentiation. Flow cytometry is used extensively to examine immune cells in non-lymphoid tissues. 2006. PubMed Boyman, O., et al. Previous studies in psoriatic human skin have described a subset of skin macrophages that migrate to the dermal/epidermal border where they communicate with epidermal keratinocytes, terming these cells epithelium-lining macrophages (24, 34). We analyzed profibrotic cells during mouse skin wound healing, fibrosis, and aging and identified distinct subpopulations of myofibroblasts, including adipocyte precursors (APs). 1994. 2004. Rupec, R. Skin graft survival and antidonor rat humoral responses were quantified. Light microscopic pictures were taken with a Leica DM 4000B microscope (Leica Microsystems) coupled to a KY-F75U digital camera (JVC) using the program Diskus 4.50 (Carl H. Hilgers). Phone: 49-221-478-86360; Fax: 49-221-478-5949; E-mail: Examination of more than 100 skin sections of more than 20 different K14-Cre-IKK2fl/fl mice revealed that F4/80-positive macrophages often accumulated directly at the interface between epidermis and dermis (Figure 2, L and M). A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. JCI Light microscopical (top 4 panels) and confocal images (bottom 12 panels) of paraffin-embedded skin sections obtained from mice of the indicated genotypes at P7. Attach 25-G needle and inject 2 ml of the solution per mouse into the peritoneal cavity. The identity of the immune cell populations that are able to induce psoriasis in humans has, however, not been fully clarified (14), and human psoriasis is still defined by clinical and histopathological criteria, the murine correlates of which we have found in the skin of K14-Cre-IKK2fl/fl mice (18). Priming caused an increase of M1 macrophage and DC populations in skin abscesses, but a decrease in the total B cell population in skin (Fig. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. Nickoloff, B.J. Whereas staining for K14 was still enhanced in the suprabasal epidermal compartment, expression of K10 and the late differentiation markers loricrin and filaggrin were restored to normal in clodronate liposome–injected mice compared with control liposome–injected mice (Figure 4). Blessing, M., Schirmacher, P., Kaiser, S. 1996. Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis. This site needs JavaScript to work properly. Here we show an essential role for skin macrophages in the development of the psoriasis-like hyperproliferative, inflammatory skin disease of K14-Cre-IKK2fl/fl mice. In: Segura E., Onai N. (eds) Dendritic Cell Protocols. JCI 2003. The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Fluorescent stainings were analyzed using a Leica TCS SP2 upright confocal laser-scanning microscope (Leica Microsystems) at excitation wavelengths of 488 nm and 543 nm. (A) RNA from mouse skin macrophages (skin mac), Kupffer cells (Kupffer), microglia from glial culture, and thioglycollate-elicited peritoneal macrophages (thio-pMac), was subjected to real-time RT-PCR for Axl, Mer, Tyro3, and Tim4. These mice had normal skin (18). Clodronate itself is nontoxic and in its free form is widely used as a drug for the treatment of malignant hypercalcemia and painful bone metastases. Pasparakis, M., et al. 5Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany. Front Cell Dev Biol. Epithelium- lining macrophages in psoriasis. 3Institute for Genetics, University of Cologne, Cologne, Germany. We conclude that the migration of granulocytes into the skin observed in K14-Cre-IKK2fl/fl mice depends on the presence of elevated numbers of skin macrophages but is not required for the development of the psoriasis-like skin disease in these mice. Provide a possible explanation for the generation of psoriais skin lesions of flaky skin.! 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