Activation of NLRP3 inflammasome in macrophages by mycoplasmal lipoproteins and lipopeptides

作者：Saeki A; Sugiyama M^*; Hasebe A; Suzuki T; Shibata K^*

来源：Molecular Oral Microbiology, 2018, 33(4): 300-311.

DOI：10.1111/omi.12225

• FSL-1
• interleukin-1
• Mycoplasma pneumoniae
• Mycoplasma salivarium
• mycoplasmal lipoproteins
• nucleotide-binding oligomerization domain-like receptor family
• pyrin domain containing 3

The NLRP3 inflammasome, an intracellular sensor consisting of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and procaspase-1, plays critical roles in host defense against microbial pathogens by inducing production of interleukin-1 (IL-1) and IL-18. Mycoplasma salivarium and Mycoplasma pneumoniae cells activated murine bone marrow-derived macrophages (BMMs) to induce production of IL-1, IL-1, and IL-18. The IL-1 production-inducing activities of these mycoplasmas toward BMMs from Toll-like receptor 2 (TLR2)-deficient mice were significantly attenuated compared with those from C57BL/6 mice (B6BMMs). This result suggests the possibility that their lipoproteins as TLR2 agonists are involved in the activity. Lipoproteins of M.salivarium and M.pneumoniae (MsLP and MpLP), and the M.salivarium-derived lipopeptide FSL-1 induced IL-1 production by B6BMMs, but not by BMMs from caspase-1-, NLRP3- or ASC-deficient mice. The activities of MsLP and MpLP were not downregulated by the proteinase K treatment, suggesting that the active sites are their N-terminal lipopeptide moieties. B6BMMs internalized the mycoplasmal N-terminal lipopeptide FSL-1 at least 30min after incubation, FSL-1-containing endosomes started to fuse with the lysosomes around 2hours, and then FSL-1 translocated into the cytosol from LAMP-1(+) endosomes. The artificial delivery of FSL-1 into the cytosol of B6BMMs drastically enhanced the IL-1 production-inducing activity. FSL-1 as well as the representative NLRP3 inflammasome activator nigericin induced the NLRP3/ASC speck, but FSL-1 located in a compartment different from the NLRP3/ASC speck.

• 出版日期2018-8