Human IL-32 expression protects mice against a hypervirulent strain of <i>Mycobacterium tuberculosis</i>

다국어 초록 (Multilingual Abstract)

<P><B>Significance</B></P><P>Interleukin-32 (IL-32) is induced by IL-1β, Toll-like receptor agonists, and nucleotide oligomerization domain as well as by <I>Mycobacterium tuberculosis</I> (<I>MTB</I>). Expression of human IL-32γ in the lungs of mice reduced the burden of <I>MTB</I> in both the lungs but also in the spleen and was associated with increased survival. Mechanistically, increased numbers of host-protective innate and adaptive immune cells were present in the IL-32 transgenic mice. Alveolar macrophages from the transgenic mice were also better able to control <I>MTB</I> infection and had increased colocalization of <I>MTB</I> with lysosomes. IL-32 expression was increased in the surgically resected lungs of tuberculosis patients, particularly in macrophages, airway epithelial cells, B cells, and T cells. Thus, IL-32 enhances host immunity against <I>MTB</I>.</P><P>Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of <I>Mycobacterium tuberculosis</I> (<I>MTB</I>) but the role of IL-32 in vivo against <I>MTB</I> remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human <I>IL-32γ</I> gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of <I>MTB</I> (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer <I>MTB</I> in the lungs and 49% and 68% fewer <I>MTB</I> in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32γTg mice, including tumor necrosis factor-alpha (TNFα) positive lung macrophages and dendritic cells, and IFN-gamma (IFNγ) and TNFα positive CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with <I>MTB</I> ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled <I>MTB</I> with lysosomes. Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32β were better able to limit <I>MTB</I> growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to <I>MTB</I>.</P>