Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice

Although T cell dysregulation is thought to underlie the pathogenesis of ps oriasis, prominent infiltration and microabscess formation by neutrophils i s a distinctive hallmark feature of this common disorder. The exact role of neutrophils in the pathogenesis of psoriasiform alterations in vivo, howev er, is unknown. Similar to human psoriasis, flaky skin mice (fsn/fsn) revea led a prominent infiltrate of neutrophils, and microabscesses within the hy perproliferative epidermis were associated with de novo expression of inter cellular adhesion molecule-1. Intraperitoneal injection with the neutrophil -depleting RB6-8C5 monoclonal antibody (anti-Ly-6G) resulted in a dramatic reduction of the epidermal thickness by 58% compared with isotype-treated a nimals (p < 0.001). In addition, epidermal microabscesses were conspicuousl y absent (p < 0.001), and cutaneous neutrophils and T cells, but not mast c ells or dendritic cells, were markedly reduced in anti-Ly-6G-treated mice. Proinflammatory cytokines, including tumor necrosis factor alpha and interl eukin-1, were also downregulated. Therapeutic effects occurred as early as 4 d after beginning of treatment. Wildtype skin was not affected. When the integrin alpha(M)beta(2) (CD11b/CD18), which mediates neutrophil l ocalization through binding to intercellular adhesion molecule-1, was block ed in vivo with the M1/70 monoclonal antibody, the epidermal thickness was reduced by 31% (p < 0.002), and neutrophil and T cell accumulation was dimi nished compared with control animals. Likewise, treatment of fsn/fsn mice w ith the MP1-22E9 monoclonal antibody neutralizing granulocyte macrophage-co lony stimulating factor, a cytokine stimulating neutrophils by upregulating alpha(M)beta(2), resulted in significant reduction of inflammation and aca nthosis by 30% (p < 0.003). These results demonstrate a critical pathogenic role of neutrophils for hyperproliferative inflammatory lesions in fsn/fsn mice, suggesting that blocking neutrophil function may have therapeutic be nefit in some human skin disorders.