Targeting mTOR in myeloid cells prevents infection-associated inflammation
Toner Y, Munitz J, Prevot G, Morla-Folch J, Wang W, van Elsas Y, Priem B, Deckers J, Anbergen T, Beldman T, Brechbühl E, Aksu M, Ziogas A, Sarlea S, Ozturk M, Zhang Z, Li W, Li Y, Maier A, Fernandes J, Cremers G, van Genabeek B, Kreijtz J, Lutgens E, Riksen N, Janssen H, Söntjens S, Hoeben F, Kluza E, Singh G, Giamarellos-Bourboulis E, Schotsaert M, Duivenvoorden R, van der Meel R, Joosten L, Cai L, Temel R, Fayad Z, Mhlanga M, van Leent M, Teunissen A, Netea M, Mulder W
Published in
Iscience: Volume 28, Issue 4, Page 112163
Abstract
Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using (18)F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.
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