Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation

Abstract

The CD18 hypomorphic (CD18 hypo ) PL/J mouse model clinically resembling human psoriasis is characterized by reduced expression of the common chain of b 2 integrins (CD11/CD18) to only 2-16% of WT levels. Previously we found that this chronic psoriasiform skin inflammation also depends on the presence of CD4 + T cells. Herein we investigated the role of macrophages in this CD18 hypo mouse model. Activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18 hypo mice and were identified as being an important source of TNF-a in vivo. Both depletion of macrophages and neutralization of TNF-a resulted in a significant alleviation of psoriasiform skin inflammation. As monocyte chemotactic protein 1 was enhanced in lesional skin of affected CD18 hypo mice, we intradermally injected recombinant murine monocyte chemotactic protein-1 (rJE/MCP-1) alone or in combination with rTNF-a into the skin of healthy CD18 hypo mice. Only simultaneous injection of rJE/MCP-1 and rTNF-a, but neither substance alone, resulted in the induction of psoriasiform skin inflammation around the injection sites with recruitment and activation of macrophages. Collectively, our data suggest that maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with sufficient release of TNF-a.

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).…”

Colony-Stimulating Factor-1 Promotes Kidney Growth and Repair via Alteration of Macrophage Responses

“…3 Embryonic macrophages appear to play a positive trophic role that may have parallel reparative functions in many adult tissues undergoing repair and cellular replacement. 1,20 A number of studies have suggested that infiltrating macrophages along with the trophic factors they release participate in tissue repair of the kidney, 20 -22 brain, 23 skin, 24,25 lung, 26 liver, 27 heart, 28 gastrointestinal tract, 29,30 and skeletal muscle. 31,32 Indeed, the pleiotrophic roles for CSF-1 in reproduction, development of multiple organ systems, and maternal-fetal interactions during pregnancy by macrophage-mediated processes have also been well defined.…”

Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

“…However, macrophage-derived proinflammatory mediators such as TNF-␣ may play a crucial role in human psoriasis (3) and in mouse models of psoriasis (4 -6). Accordingly, selective depletion of macrophages by liposome-encapsulated clodronate in mouse models and treatment of the patients with the TNF-␣ antagonist etanercept resulted in improvement of skin inflammation in murine models and human psoriasis (4,5,7). Apart from TNF-␣, a considerable number of cytokines, including the NF-B-induced IL-12, IL-15, IL-20, and IL-23 as well as IFN-␣ and IFN-␤, have been shown to participate in the pathogenesis of psoriasis (8,9).…”

“…The active form of NF-B is a dimer formed by members of the NF-B/Rel family of proteins, with the p50/p65 dimer being the most abundant. Phosphorylation of the inhibitor IB by the IB kinase (IKK) 4 complex is a central step in NF-B activation, leading to IB degradation and subsequent nuclear translocation of p50/p65 and other NF-B subunits (10,13). The transcriptional activity of the p50/p65 dimer is further enhanced by the IKKdependent phosphorylation of p65 on Ser 536 (13,14).…”