Psoriasis is currently an incurable skin disorder mainly driven by a chronic inflammatory response. We found that subcutaneous application of umbilical cord- derived mesenchymal stem/stromal cells (MSCs) primed by IFN-γ and TNF-α, referred to as MSCs-IT, exhibited remarkable therapeutic efficacy on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Neutrophil infiltration, a hallmark of psoriasis, was significantly reduced after treatment with MSCs-IT. We further demonstrated that the effects of MSCs-IT were mediated by tumor necrosis factor (TNF) stimulating gene-6 (TSG-6), which was greatly upregulated in MSCs upon IFN-γ and TNF-α stimulation. MSCs transduced with TSG-6 siRNA lost their therapeutic efficacy while recombinant TSG-6 applied alone could also reduce neutrophil infiltration and alleviate the psoriatic lesions. Furthermore, we demonstrated that TSG-6 could inhibit neutrophil recruitment by decreasing the expression of CXCL1, which may be related to the reduced level of STAT1 phosphorylation in the keratinocytes. Thus, blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.

Systemic sclerosis (SSc) is a recalcitrant autoimmune disease for which there is no cure. Mesenchymal stem cell (MSC)-based treatment has emerged as a promising therapeutic option for several autoimmune diseases. Previously, we found that the immunoregulatory potential of MSCs can be greatly enhanced by IFN-γ and TNF-α. Here, we found that IFN-γ- and TNF-α-pretreated MSCs significantly alleviated skin fibrosis in a bleomycin (BLM)-induced SSc model. Macrophages were found to be the predominant profibrotic immune cell population in the pathogenesis of SSc. The accumulation of macrophages was significantly decreased by MSC treatment. Importantly, MSCs primarily reduced the population of maturing macrophages with high CCR2 expression by inhibiting the generation of CCL2 from fibroblasts and macrophages. This finding may help to improve MSC-based clinical treatments for SSc patients.

Systemic sclerosis (SSc) is a recalcitrant autoimmune disease characterized by progressive fibrosis in the skin and internal organs, such as the lungs. A key feature of this disease is the infiltration of innate immune cells, yet, how they contribute to the pathogenesis of SSc is largely unknown. Here, we demonstrated that the CD206hiMHCIIlo macrophages were the dominant immune cell population accumulated in the fibrotic skin of SSc mice, and these cells were found to be critical in mediating the profibrotic response by producing TGF-β1 in a MerTK signaling-dependent manner. Interestingly, the neutrophil infiltration was a prerequisite for the accumulation of CD206hiMHCIIlo macrophages and depletion of neutrophils or inhibition of CXCR1/2 could reduce CD206hiMHCIIlo macrophages and alleviate SSc progression. Detailed investigations revealed that in the fibrotic skin, neutrophils released neutrophil extracellular traps (NETs) ensnared macrophages and were responsible for the differentiation of CD206hiMHCIIlo macrophages. Our findings uncovered a key role of the neutrophil-macrophage-fibrosis axis in the pathogenesis of SSc and provide critical information for the development of novel therapeutic strategies.