Coordinated Regulation of TLR2 Signaling by Neu1 Sialidase and the Siglec-5/Siglec-14 Receptor Pair During <i>Mycoplasma pneumoniae</i> Infection

Mycoplasma pneumoniae is a primary cause of community-acquired pneumonia, characterized by an excessive host inflammatory response that often drives lung pathology. While Toll-like receptor 2 (TLR2) is the principal sensor for this pathogen, the regulatory mechanisms that calibrate its signaling intensity remain incompletely understood. In this study, we delineate a novel disinhibition-amplification network controlling the macrophage response to M. pneumoniae . We demonstrate that TLR2 engagement triggers the secretion of Matrix metalloproteinase-9 (MMP-9), which subsequently activates the host sialidase Neu1. Activated Neu1 translocates to the cell surface and disrupts the constitutive inhibitory interaction between Siglec-5 and TLR2, effectively releasing a molecular brake. Concurrently, infection induces the specific upregulation of the activating receptor Siglec-14. We reveal that Siglec-14 physically interacts with TLR2 and recruits the Spleen Tyrosine Kinase (Syk) to the plasma membrane. Crucially, this Siglec-14/Syk axis functions as a necessary molecular scaffold that amplifies and sustains MAPK and NF-κB signaling. Disruption of this network, either by silencing Neu1 or Siglec-14, significantly attenuates the inflammatory response. These findings identify the Siglec-5/Siglec-14 receptor pair as a critical checkpoint in mycoplasma pathogenesis and suggest that targeting the MMP9-Neu1-Siglec-14 axis offers a new therapeutic strategy to mitigate inflammation-mediated lung damage.