Recent studies have uncovered the pivotal role of locally produced complement in shaping the adaptive immune responses and in modulating tissue damage in peripheral organs. However, the function played by complement during skin inflammation remains poorly understood. To investigate this, I used a model of psoriasis induced by the topical application of TLR-7 agonist 5% Imiquimod cream (IMQ). In the absence of C3, psoriatic clinical features were significantly attenuated, consistently with a contracted skin neutrophil infiltrate and production of IL-17 by gamma-delta T cells. In the skin of WT IMQ-treated animals, C3 was present only in the dermis, suggesting that C3 may act in this model as a mediator of the cross-talk between stromal cells and the innate-adaptive immune response. Guided by these observations, I then explored whether the different local inflammatory response observed in C3-/- mice translated also in altered systemic inflammation in a model of autoimmunity induced by long-term topical application of IMQ. I found that IMQ generated only a mild autoimmune response, and this was not influenced by the lack of C3. While IMQ failed to trigger an overt autoimmune response, the prolonged topical stimulation of TLR7 with R848 led to a striking monocytosis and to systemic lupus erythematosus (SLE)-features. These effects were unique to the topical application of R848 and were not influenced by the lack of C3 or C1q. Topical R848 induced a rapid enhancement of the bone marrow myelopoiesis. The monocytosis occurred independently of IFN-alpha, IL-1, CX3CR1 and CCR2, two crucial receptors involved in monocyte trafficking and homeostasis. My findings suggest a novel role for cutaneous TLR7 activation in promoting systemic immune changes. As viral ssRNA and endogenous nucleic acids represent TLR7 ligands, this model recapitulates SLE exacerbations induced by viral agents or excessive apoptosis in the skin secondary to UV-exposure.