Abstract
Alteration of macrophage function has an important regulatory impact on the survival of intracellular mycobacteria. We found that macrophages infected with attenuated Mycobacterium tuberculosis (Mtb) strain H37Ra had elevated expression of M1-related molecules, whereas the M2 phenotype was dominant in macrophages infected with virulent Mtb H37Rv. Further, the TLR signalling pathway played an important role in modulating macrophage polarization against Mtb infection. Interestingly, endoplasmic reticulum (ER) stress was significantly increased in M1 polarized macrophages and these macrophages effectively removed intracellular Mtb, indicating that ER stress may be an important component of the host immune response to Mtb in M1 macrophages. This improved understanding of the mechanisms that regulate macrophage polarization could provide new therapeutic strategies for tuberculosis.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health problem
To investigate changes in macrophage phenotype that result from mycobacterial infection, bone marrow derived macrophages (BMDMs) were infected either with virulent Mtb H37Rv or attenuated Mtb H37Ra at a multiplicity of infection (MOI) of 1, and macrophage phenotypes were monitored
During Mtb infection, apoptosis and activation of macrophages are important events that reduce the number of intracellular Mtb[1,18,22]
Summary
Mtb infection may regulate characterization of macrophages. To investigate changes in macrophage phenotype that result from mycobacterial infection, bone marrow derived macrophages (BMDMs) were infected either with virulent Mtb H37Rv or attenuated Mtb H37Ra at a multiplicity of infection (MOI) of 1, and macrophage phenotypes were monitored. The combination of these two factors induced M2-like types in M1-polarized macrophages by H37Ra infection, as indicated by increase STAT3 phosphorylation and decrease in STAT1 and iNOS activation (Fig. 1l,m) These data suggest that virulent mycobacteria can skew the macrophage function toward the M2 phenotype, through the production of ESAT-6, to manipulate the environment for survival in the host. CHOP knockdown and 4-phenylbutyrate (4PBA) pre-treatment decreased H37Ra-induced CHOP expression and apoptosis in M1 macrophages (Fig. 4d–f) These results show that ER stress-mediated apoptosis is more associated with M1-polarized macrophages than M2 macrophages during Mtb infection. Pre-treatment with 4PBA increased the intracellular survival of H37Ra in M1 macrophages, but not in M2 macrophages, suggesting that M1-polarized cells are closely associated with ER stress to regulate intracellular mycobacteria (Fig. 5g). This result indicates that M1 macrophage polarization contributes to the elimination of intracellular mycobacteria
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