Intervention of Inflammatory Monocyte Activity Limits Dermal Fibrosis

Abstract Monocytes and monocyte-derived cells are important players in the initiation, progression and resolution of inflammatory skin reactions. As inflammation is a pre-requisite for fibrosis development, we focused on the role of monocytes in cutaneous fibrosis, the clinical hallmark of patients suffering from systemic sclerosis. Investigating the function of monocytes in ROS-induced dermal fibrosis, we observed that early monocyte depletion partially reduced disease severity. Low numbers of inflammatory Ly6C high monocytes as well as CCR2/CCL2 inhibition in WT animals by a specific L-RNA aptamer mitigated disease parameters, indicating a pivotal role for CCR2 + inflammatory monocytes and the CCR2/CCL2 axis in fibrosis development. Of note, mice lacking splenic reservoirs failed to recruit monocytes to the skin and developed less fibrosis. Furthermore, enforced monocyte conversion into non-inflammatory, patrolling Ly6C low monocytes by a nuclear receptor Nur77 (NR4A1) agonist also resulted in significantly impaired cutaneous inflammation and dermal fibrosis. Most evident, pronounced monocyte conversion in interferon stimulated gene 12 (ISG12)-deficient mice with pronounced nuclear Nur77 signaling completely protected from dermal fibrosis. Our study shows that inflammatory monocytes that are recruited from splenic reservoirs play a key role in the development of skin fibrosis and can be therapeutically challenged by forced conversion via the Nur77/ISG12 axis.