Immunosuppressive functions of M2 macrophages derived from iPSCs of ALS patients and healthy controls

SUMMARY Amyotrophic 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, M2 have not been investigated in ALS, nor have human-iPSC-derived M2 been thoroughly studied for immunosuppressive potentials. Here, C9orf72 mutation or sporadic ALS patients’ iPSCs 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 ALS patients’ Tregs 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. This study demonstrates that M2 cells differentiated from ALS patients’ iPSCs are immunosuppressive, boost ALS Tregs, and may serve as a candidate for immune-cell-based therapy to mitigate inflammation in ALS.