摘要：SummaryAmyotrophic lateral sclerosis (ALS) is a disorder with immune alterations that augment disease severity. M2 macrophages benefit diabetic and nephrotic mice by suppressing the pro-inflammatory state. However, neither have M2 cells been investigated in ALS nor have human induced pluripotent stem cell (iPSC)-derived M2 cells been thoroughly studied for immunosuppressive potentials. Here, iPSCs of C9orf72 mutated or sporadic ALS patients were differentiated into M2 macrophages, which suppressed activation of pro-inflammatory M1 macrophages as well as proliferation of ALS CD4+CD25-Tc (Teffs). M2 cells converted ALS Teffs into CD4+CD25+Foxp3+regulatory T cells (Tregs) and rescued Tregs of ALS patients from losing CD25 and Foxp3. Furthermore, Tregs induced or rescued by iPSC-derived M2 had strong suppressive functions. ALS iPSC-derived M2 cells including those with C9orf72 mutation had similar immunomodulatory activity as control iPSC-derived M2 cells. This study demonstrates that M2 cells differentiated from iPSCs of ALS patients are immunosuppressive, boost ALS Tregs, and may serve as a candidate for immune-cell-based therapy to mitigate inflammation in ALS.Graphical AbstractDisplay OmittedHighlights•ALS iPSC-derived M2 inhibit M1 activation and proliferation of ALS effector T cells•ALS iPSC-derived M2 induce functional Tregs from ALS effector T cells•ALS iPSC-derived M2 sustain ALS Tregs' function and phenotypic expression•Functions of sporadic ALS, C9 mutant ALS, and control iPSC-derived M2 are comparableCellular Neuroscience; Immunology
