Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Abstract

Summary Macrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors. We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatment of primary macrophages with rocaglates enhanced phagosome-lysosome fusion and control of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization toward the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., chronic bacterial infections, allergies, and, possibly, certain tumors.

Synthetic flavagline derivative 1‐chloroacetylrocaglaol promotes apoptosis in K562 erythroleukemia cells through miR‐17‐92 cluster genes

“…In this study, preclinically, a novel flavagline derivative (A2074) was estimated as a significant drug of choice for CML treatment. Flavaglines exhibit a wide variety of bioactivities [ 17 ] ranging from antiviral, [ 18–20 ] antifungal, [ 21 ] antiprotozoal, [ 22 ] anti‐inflammatory activities, [ 23 ] and antiproliferative [ 24,25 ] properties. Numerous flavaglines have been determined as regulators of cell death, exerting significant cytotoxicity against cancerous cells as activators of apoptosis.…”

“…In this study, preclinically, a novel flavagline derivative (A2074) was estimated as a significant drug of choice for CML treatment. Flavaglines exhibit a wide variety of bioactivities [17] ranging from antiviral, [18][19][20] antifungal, [21] antiprotozoal, [22] antiinflammatory activities, [23] and antiproliferative [24,25] properties.…”

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

“…Other hub-central gene of the brown module, including CSF1 ( Chatterjee et al, 2021 ), PLAUR ( McLoughlin et al, 2021b ), ITGB1 ( Yang et al, 2017 ), CCND1 ( Koo et al, 2012 ; Looney et al, 2021 ), CSF2 ( Marsay et al, 2013 ; Shukla et al, 2017 ; Abdelaal et al, 2022 ), CTLA4 ( Zhang et al, 2021 ), FLNA ( Xu et al, 2015 ), CCND2 ( Lavalett et al, 2017 ), WEE1 ( Jayaswal et al, 2010 ), MMP9 ( Blanco et al, 2012 ; McLoughlin et al, 2014 ), CDC25A ( Shapira et al, 2020 ), CSF2RB ( Benmerzoug et al, 2018 ), TIMP1 ( Sun et al, 2020 ), CD69 ( Li et al, 2011 ; Chen et al, 2020 ), PTPN22 ( Boechat et al, 2013 ), CD38 ( Silveira-Mattos et al, 2019 ), IL7R ( Jenum et al, 2016 ; Alsulaimany et al, 2022 ), IL1RN ( Alcaraz-López et al, 2020 ), and IDO1 ( Weiner et al, 2012 ; Gautam et al, 2018 ) were also involved in host-pathogen interactions as well as suppression of host immune response. For example, the CTLA4 hub-central gene encodes an inhibitor of T cell-mediated response ( Schneider et al, 2006 ), and the upregulation of this gene in response to M. bovis infection may reflect a mechanism of immunomodulation used by M. bovis to subvert a host T-cell response ( Killick et al, 2011 ).…”

Macrophage plasticity as a therapeutic target in tuberculosis

“…Similarly, in a recent study, treatment with rocaglates, a natural compound isolated from Aglaia species, contributes to inhibition of Erk‐dependent M2 polarization with concomitantly increased response to IFNγ via p38 activation. Also, the rocaglates‐treated mice's bone marrow‐derived macrophages results in an effective M. tb clearance [57].…”