MTOR inhibitor INK128 attenuates systemic lupus erythematosus by regulating inflammation-induced CD11b+Gr1+ cells

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Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by systemic chronic inflammation that can affect multiple major organ systems. Although the etiology of SLE is known to involve a variety of factors such as the environment, random factors and genetic susceptibility, the exact role of CD11b+Gr1+ myeloid cells in lupus progression is not fully understood. Myeloid-derived CD11b+Gr1+ cells are thought to be a heterogeneous group of immature myeloid cells with immune function. Some studies have reported that CD11b+Gr1+ cells and the activation of mTOR pathway are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, it is still not clarified about the mechanism of influence of lupus microenvironment and mTOR signaling on CD11b+Gr1+ cells. In the present study, we found that the percentage of CD11b+Gr1+ cells increased prior to the abnormal changes of Th17, Treg, T and B cells during lupus development. TLR7 and IFN-α signaling synergized to promote CD11b+Gr1+ cell accumulation in an mTOR-dependent manner. Moreover, compared to a traditional mTOR inhibitor, INK128 inhibited more effectively the disease activity via regulating CD11b+Gr1+ cell expansion and functions. Furthermore, TLR7/IFN-α-modified CD11b+Gr1+ cells promoted unbalance of Th17/Tregs and were inclined to differentiate into macrophages via the mTOR pathway. In conclusion, CD11b+Gr1+ cells increased in the early stages of the lupus progression and mTOR pathway was critical for CD11b+Gr1+ cells in lupus development, suggesting the changes of inflammation-induced CD11b+Gr1+ cells initate lupus development. We also provide evidence for the first time that INK128, a second generation mTOR inhibitor, has a good therapeutic action on lupus development by regulating CD11b+Gr1+ cells.