S100A12: Friend or foe in pulmonary tuberculosis?

In humans, S100A12 (also named Calgranulin C and EN-RAGE) is mainly expressed and secreted by neutrophil granulocytes. Extracellular S100A12 is involved in innate immune responses against microorganisms and parasites. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), which is a cell surface receptor on macrophages, endothelium, and lymphocytes. In a recent study, Realegeno et al. showed that S100A12 exerts antimicrobial activity against Mycobacterium leprae in infected human macrophages. Recently, some interesting data on the antimicrobial activity of S100A12 have been reported. Proinflammatory role of S100A12 is supported by another newly found receptor, Toll-like receptor 4 (TLR4). These observations emphasize the importance of S100A12 for the development of potential therapeutic approaches to increase protective immunity or reduce immunopathogenesis.

S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.