IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis

Abstract

BackgroundIntracellular bacterium, Mycobacterium tuberculosis (M. tb), infects specifically macrophages as host cells. IRAK-M, a member of IRAK family, is a negative regulator in TLR signaling and specifically expresses in monocytes and macrophages. The role of IRAK-M in intracellular growth of M. tb and macrophage polarization was explored, for deeply understanding the pathogenesis of M. tb, the significance of IRAK-M to innate immunity and pathogen-host interaction.MethodsIRAK-M expression was detected in M. tb infected macrophages and in human lung tissue of pulmonary tuberculosis with immunofluorescence staining, Western blot and immunohistochemistry. IRAK-M knock-down and over-expressing cell strains were constructed and intracellular survival of M. tb was investigated by acid-fast staining and colony forming units. Molecular markers of M1-type (pSTAT1 and iNOS) and M2-type (pSTAT6 and Arg-1) macrophages were detected using Western blot in IRAK-M knockdown U937 cells infected with M. tb H37Rv. U937 cells were stimulated with immunostimulant CpG7909 into M1 status and then infected with M. tb H37Rv. Expression of IRAK-M, IRAK-4 and iNOS was detected with immunofluorescence staining and Western blot, to evaluate the effect of IRAK-M to CpG directed M1-type polarization of macrophages during M. tb infection. Molecules related with macrophage’s bactericidal ability such as Hif-1 and phosphorylated ERK1/2 were detected with immunohistochemistry and Western blot.ResultsIRAK-M increased in M. tb infected macrophage cells and also in human lung tissue of pulmonary tuberculosis. IRAK-M over-expression resulted in higher bacterial load, while IRAK-M interference resulted in lower bacterial load in M. tb infected cells. During M. tb infection, IRAK-M knockdown induced M1-type, while inhibited M2-type polarization of macrophage. M1-type polarization of U937 cells induced by CpG7909 was inhibited by M. tb infection, which was reversed by IRAK-M knockdown in U937 cells. IRAK-M affected Hif-1 and MAPK signaling cascade during M. tb infection.ConclusionsConclusively, IRAK-M might alter the polarity of macrophages, to facilitate intracellular survival of M. tb and affect Th1-type immunity of the host, which is helpful to understanding the pathogenesis of M. tb.

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

“…M2 macrophages are deleterious to the host, as they fail to eradicate M. tuberculosis bacilli (Huang et al, 2015(Huang et al, , 2018. Overexpression of IL-1R-associated kinase M (IRAK-M), a negative regulator of Toll-like receptor (TLR) pathways, has been reported in the lungs of tuberculosis patients, and in vitro IRAK-M modulation is associated with the M2 phenotype and reduced M. tuberculosis control (Shen et al, 2017). M2 macrophages also secrete most type 2 cytokines such as IL-10, which inhibit type 1 cytokines TNFa, IFNg, and IL-12.…”

Macrophage heterogeneity and plasticity in tuberculosis

“…Shen et al. showed increased expression of IRAK‐M in M. tuberculosis infected human macrophages and in lung tissue of tuberculosis patients . Overexpression of IRAK‐M in macrophages resulted in higher bacterial load, while blocking IRAK‐M resulted in a lower bacterial load, indicating that increased expression of IRAK‐M might alter the polarity of macrophages toward the M2 phenotype.…”

“…Very little is known about the mechanisms through which M. tuberculosis alters the macrophage phenotype. One of the suggested mechanisms involves M. tuberculosis utilizing IL‐1 receptor‐associated kinase restricted to monocytic cells (IRAK‐M) to direct macrophage polarity to facilitate its intracellular survival . IRAK‐M is an inhibitory, inactive form of IRAK, which is known to play a critical role in the regulation of innate immunity .…”

HIV and the tuberculosis “set point”: how HIV impairs alveolar macrophage responses to tuberculosis and sets the stage for progressive disease

“…The GM-CSF:M-CSF balance is also altered by the presence of Mtb [ 81 ] and M-CSF-driven macrophages are more permissive to Mtb replication and dissemination [ 82 ]. Similarly, interleukin-1 receptor-associated kinase M (IRAK-M), which is downstream of the GM-CSF-dependent transcription factor PU.1, correlates directly with mycobacterial load in human lung tissue and impacts Mtb survival [ 83 ]. Thus, the combined impact of Mtb and HIV on the balance of cytokines within the lungs leads to an environment that permits the growth of both pathogens.…”