IL-23 is a pleiotropic cytokine which is involved in many autoimmune diseases including psoriasis and psoriatic arthritis [1,2]. IL-23 is critical for a plethora of immune responses, including the differentiation, survival, and expansion of Th17, γδ T cells and neutrophils [3,4]. Although the effects of IL-23 in the lymphoid cells have been extensively studied in relation to IL-17A production, less is known regarding the effects of IL-23 on myeloid cells. Despite multiple studies demonstrating the importance of IL-23 and its effector signaling in myelopoiesis and the recruitment and activation of neutrophils, the exact cellular and molecular pathways that govern pathogenesis remain elusive [[4], [5], [6], [7], [8]].

We have previously demonstrated that IL-23 induces myelopoiesis in the bone marrow and induces Myeloid DAP12-associated lectin 1 (MDL-1) which is associated with osteoclast activation and arthritis [[9], [10], [11]]. MDL-1 also known as CLEC5A is a C-type lectin, (herein referred to as MDL-1) is exclusively expressed on myeloid cells and is a major PU.1 transcriptional target during myeloid differentiation regulating a number of myeloid-dependent immune and inflammatory responses including differentiation, activation and cell recruitment during inflammation [9,[12], [13], [14], [15]]. Flaviviruses and Listeria monocytogenes stimulate MDL-1 to induce proinflammatory cytokine production [16,17], canonical inflammasome activation and neutrophil extracellular trap (NET) formation [18,19], while MDL-1 deficiency impairs the development of intestinal γδ T cells after L. monocytogenes infection [19]. MDL-1 is a key regulator of synovial injury and bone erosion during autoimmune joint inflammation [9] and dengue virus infection [20]. Furthermore, MDL-1+ immature myeloid cells are responsive for ConA-induced liver inflammation [21]. All these observations suggest that MDL-1 plays a critical role in septic and aseptic inflammatory reactions.

Herein, we show that genetic ablation of MDL-1 prevents IL-23-induced skin inflammation demonstrating the importance of myelopoiesis in IL-23-induced pathology. Our data show that MDL-1 is critical for the development and maturation of promyelocytes to IL-17A+ neutrophils in the skin that regulate skin pathology. Collectively our data demonstrate MDL-1 as a transcriptional target in IL-23-induced skin pathology that can be exploited for therapeutic intervention.