Identification of compounds that decrease numbers of Mycobacteria in human macrophages in the presence of serum amyloid P.
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abstract
Ms are a heterogeneous population of cells and include classically activated Ms (M1) and alternatively activated Ms (M2). Ms can change from M1 to M2 and vice versa in response to environmental stimuli. Serum amyloid P (SAP) is a constitutive plasma protein that polarizes Ms to an M2 phenotype, and part of this effect is mediated through FcRI receptors. In an effort to find ways to alter Ms phenotypes, we screened for compounds that can block the SAP-FcRI interaction. From a screen of 3000 compounds, we found 12 compounds that reduced the ability of fluorescently labeled human SAP to bind cells expressing human FcRI. Based on cell surface marker expression, 8 of the compounds inhibited the effect of SAP on skewing human Ms to an M2 phenotype and in the presence of SAP polarized Ms to an M1 phenotype. In diseases, such as tuberculosis, M1s are more effective at killing bacteria than M2s. SAP potentiated the numbers of the mycobacterial strains Mycobacterium smegmatis and Mycobacterium tuberculosis in Ms. When added along with SAP, 2 of the compounds reduced intracellular Mycobacterium numbers. Together, these results indicate that the blocking of SAP effects on Ms can skew these cells toward an M1 phenotype, and this may be useful in treating diseases, such as tuberculosis.
