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Cp GB DNA activates dermal macrophages and specifically recruits inflammatory monocytes into the skin
Author(s) -
Mathes Allison L.,
Rice Lisa,
Affandi Alsya J.,
DiMarzio Michael,
Rifkin Ian R.,
Stifano Giuseppina,
Christmann Romy B.,
Lafyatis Robert
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12603
Subject(s) - chemokine , inflammation , immunology , innate immune system , immune system , dna vaccination , microbiology and biotechnology , proinflammatory cytokine , chemokine receptor , monocyte , cytokine , biology , chemistry , immunization
Toll‐like receptor 9 ( TLR 9) drives innate immune responses after recognition of foreign or endogenous DNA containing unmethylated CpG motifs. DNA ‐mediated TLR 9 activation is highly implicated in the pathogenesis of several autoimmune skin diseases, yet its contribution to the inflammation seen in these diseases remains unclear. In this study, TLR 9 ligand, Cp GB DNA , was administered to mice via a subcutaneous osmotic pump with treatment lasting 1 or 4 weeks. Gene expression and immunofluorescence analyses were used to determine chemokine expression and cell recruitment in the skin surrounding the pump outlet. Cp GB DNA skin treatment dramatically induced a marked influx of CD 11b + F4/80 + macrophages, increasing over 4 weeks of treatment, and induction of IFN γ and TNF α expression. Chemokines, CCL 2, CCL 4, CCL 5, CXCL 9 and CXCL 10, were highly induced in Cp GB DNA ‐treated skin, although abrogation of these signalling pathways individually did not alter macrophage accumulation. Flow cytometry analysis showed that TLR 9 activation in the skin increased circulating CD 11b + CD 115 + Ly6C hi inflammatory monocytes following 1 week of Cp GB DNA treatment. Additionally, skin‐resident CD 11b + cells were found to initially take up subcutaneous Cp GB DNA and propagate the subsequent immune response. Using diphtheria toxin‐induced monocyte depletion mouse model, gene expression analysis demonstrated that CD 11b+ cells are responsible for the Cp GB DNA ‐induced cytokine and chemokine response. Overall, these data demonstrate that chronic TLR 9 activation induces a specific inflammatory response, ultimately leading to a striking and selective accumulation of macrophages in the skin.