Transcriptomic and proteomic profiling of non-classical monocytes unravels distinct pathogenic features in SLE

Current non-specific immunosuppressive treatments for Systemic Lupus Erythematosus (SLE) show modest efficacy. In SLE the monocytic/macrophage (Mo/Mφ) system plays a key role in the initiation and perpetuation of the systemic autoimmune response. However, the distinct functions of the Mo/Mφ cellular subsets remain elusive. Herein, we demonstrate a distinct proteomic and transcriptomic profile of non-classical monocytes (NCM) of active patients with SLE with enhanced inflammatory features such as deregulated DNA repair, cell cycle and enhanced IFN signaling in parallel with cell differentiation and developmental cues. Ex-vivo assays revealed an upregulation of p53 due to enhanced DNA damage along with G0 cell cycle arrest of SLE NCM indicative of an inflammatory phenotype. This aberrant profile of NCM of active patients with SLE is linked with an activated macrophage-like and enriched M1 pro-inflammatory response. We envisage that enhanced autophagy in SLE NCM may drive their differentiation towards an M1-like macrophage profile contributing to disease severity. Together, these findings provide evidence of skewed differentiation of NCM towards an M1-like macrophage phenotype as a pathogenic feature of NCM in SLE.