Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation

Abstract

Psoriasis is a common skin disease, the pathogenesis of which has not yet been resolved. In mice, epidermis-specific deletion of inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2) results in a skin phenotype that mimics human psoriasis in several aspects. Like psoriasis, this skin disease shows pronounced improvement when mice are treated with a TNF-neutralizing agent. We have found previously that this phenotype does not depend on the presence of alphabeta T lymphocytes. In order to evaluate contributions of other immune cell populations to the skin disease, we selectively eliminated macrophages and granulocytes from the skin of mice with epidermis-specific deletion of IKK2 (K14-Cre-IKK2fl/fl mice). 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. The hyperproliferative, inflammatory skin disease in K14-Cre-IKK2fl/fl mice was a direct consequence of the presence of macrophages in the skin, as targeted deletion of CD18, which prevented accumulation of granulocytes but not macrophages, did not lead to major changes in the phenotype. 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. 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.

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

“…Psoriatic lesions contain mast cells (39), and complement activation is suggested to be important in disease mediation in mouse arthritis and patients with Ps (40,41), whereas the contributions of mast cells, FcγRIII, and C5 in this disease model seem to be redundant. Conversely, increased frequency of monocytes/macrophages, depletion experiments, and the suppressor function of macrophage-derived ROS clearly argue in favor of a role of monocytes/macrophages in the disease, which is in accordance with the findings in patients with the psoriatic form of skin lesions (42,43) and arthritis (22).…”

NF-κB in the regulation of epithelial homeostasis and inflammation

“…Similarly, the presence of neutrophil infiltration of the skin was not necessary for the development of skin lesions, as shown in IKK2 EKO mice crossed into a CD18-deficient background [81]. In contrast, local elimination of macrophages using subcutaneous injection of clodronate liposomes dramatically reduced inflammation in IKK2 EKO mice, showing that the development of inflammatory skin lesions in this model is largely driven by macrophages [81].…”

“…IKK2 EKO mice crossed into a TNFR1-deficient genetic background do not develop skin lesions and maintain a healthy skin for the entire durations of their lives, demonstrating that TNFR1-mediated signaling is essential for triggering skin inflammation in this model [80]. In contrast, IKK2 EKO mice crossed into an IFNγ-deficient background or in a TCRα-deficient background, developed inflammatory skin lesions showing that neither IFNγ nor the presence of αβ T cells is required for skin inflammation in this model [80,81]. Similarly, the presence of neutrophil infiltration of the skin was not necessary for the development of skin lesions, as shown in IKK2 EKO mice crossed into a CD18-deficient background [81].…”

“…In contrast, IKK2 EKO mice crossed into an IFNγ-deficient background or in a TCRα-deficient background, developed inflammatory skin lesions showing that neither IFNγ nor the presence of αβ T cells is required for skin inflammation in this model [80,81]. Similarly, the presence of neutrophil infiltration of the skin was not necessary for the development of skin lesions, as shown in IKK2 EKO mice crossed into a CD18-deficient background [81]. In contrast, local elimination of macrophages using subcutaneous injection of clodronate liposomes dramatically reduced inflammation in IKK2 EKO mice, showing that the development of inflammatory skin lesions in this model is largely driven by macrophages [81].…”

Netrin-1, a missing link between chronic inflammation and tumor progression

“…As an example, NF-κB inhibition in epidermal keratinocytes spontaneously triggers a strong inflammatory response in the skin and the development of squamous cell carcinoma. [106][107][108][109] Along the same line, in hepatocytes, NFκB provides survival signals that protect cells from toxic compounds, and its inhibition triggers liver inflammation and compensatory hepatocyte proliferation, resulting in the development of hepatocellular carcinoma. 39,110 For this reason, although strategies targeting NFκB have great potential for the treatment of inflammatory diseases, the potential side effects of NFκB blockade seem to be a major problem in bringing NFκB inhibitors to the clinic.…”