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.

激活胞内病原体（如分枝杆菌）感染的巨噬细胞中的抗菌机制，对于宿主抵御感染至关重要。为揭示先天与适应性免疫系统诱导的独特及共有抗菌网络，本研究对经Toll样受体2/1配体（TLR2/1 ligand, TLR2/1L）或干扰素γ（IFN-γ）激活的人单核细胞衍生巨噬细胞（human monocyte-derived macrophages, MDMs）的RNA测序（RNA sequencing, RNAseq）基因表达谱进行了分析。采用加权基因共表达网络分析，鉴定出与TLR2/1L或IFN-γ显著相关的基因模块，这些模块均富集于“防御反应”基因本体（gene ontology, GO）术语。TLR2/1L与IFN-γ共同诱导的人巨噬细胞宿主防御网络包含16个抗菌应答基因，其中S100A12是TLR2/1L诱导上调最为显著的基因之一。目前关于S100A12在感染性疾病中的作用的研究信息较为有限，因此我们验证了“S100A12可促进人类宿主抵御分枝杆菌感染”这一假说。本研究证实，S100A12可直接杀伤结核分枝杆菌（Mycobacterium tuberculosis）与麻风分枝杆菌（Mycobacterium leprae）。同时我们还证明，在感染巨噬细胞中，TLR2/1L与IFN-γ诱导的抗麻风分枝杆菌抗菌活性依赖于S100A12。在麻风病病灶处，我们发现S100A12在结核样型麻风（tuberculoid leprosy, T-lep，该病的自限性亚型）皮损中的表达水平显著高于瘤型麻风（lepromatous leprosy, L-lep，该病的进行性亚型）。上述数据表明，S100A12属于先天与适应性诱导的抗菌网络的组成部分，可在感染巨噬细胞中助力宿主抵御分枝杆菌感染。