Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity

Abstract

Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Several protein kinase inhibitors are available for clinical use. 129 Imatinib, a tyrosine kinase inhibitor, reduces bacterial load and lung pathology, likely by enhancing autophagy, phagosomal acidification and myeloid cell mobilization, [130][131] and is currently being tested for its safety and immunogenicity as repurposed TB treatment. Adenosine monophosphate-activated protein kinase (AMPK) regulates cellular energy levels, T-cell differentiation and development of memory.…”

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

“…The tyrosine kinase inhibitor imatinib has emerged as a host-directed therapy for TB and other infections (23, 39, 40). In human macrophages imatinib was shown to induce the v-ATPase, leading to lysosome acidification and antimicrobial activity against M. tuberculosis (23).…”

TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation

“…7,11,13,14 these subtypes were impacted by flagellin treatment, we performed flow cytometry analysis on LSK cells from flagellin-or PBS-treated WT B6 mice using the recently defined signaling lymphocytic activation molecule (SLAM) code, which is capable of distinguishing LT-HSC, ST-HSC, and MPP subtypes. 14,25,26 This cellular identification protocol indicated that flagellin did not increase the level or alter the proliferative status of LT-HSCs (supplemental Figure 7A-C). Rather, flagellin treatment drove the proliferation of ST-HSCs and myeloid precursors MPP2 and especially MPP3, whose levels increased 10-fold following flagellin treatment ( Figure 5A-E).…”

“…Markers for LT-HSCs, ST-HSCs, and MPP1-MPP4 are previously described. 14,25,26 In cell proliferation assays, intracellular staining of allophycocyanin-conjugated anti-BrdU and 7-aminoactinomycin D (7-AAD) were performed following surface staining. Stained cells were analyzed on a BD Fortessa flow cytometer.…”