<i>Mycoplasma hyopneumoniae</i> inhibits the unfolded protein response to prevent host macrophage apoptosis and M2 polarization

Enzootic pneumonia caused by <i>Mycoplasma hyopneumoniae</i> (<i>M. hyopneumoniae</i>) has inflicted substantial economic losses on the global pig industry. The progression of <i>M. hyopneumoniae</i> induced-pneumonia is associated with lung immune cell infiltration and extensive proinflammatory cytokine secretion. Our previous study established that <i>M. hyopneumoniae</i> disrupts the host unfolded protein response (UPR), a process vital for the survival and immune function of macrophages. In this study, we demonstrated that <i>M. hyopneumoniae</i> targets the UPR- and caspase-12-mediated endoplasmic reticulum (ER)-associated classical intrinsic apoptotic pathway to interfere with host cell apoptosis signaling, thereby preserving the survival of host tracheal epithelial cells (PTECs) and alveolar macrophages (PAMs) during the early stages of infection. Even in the presence of apoptosis inducers, host cells infected with <i>M. hyopneumoniae</i> exhibited an anti-apoptotic potential. Further analyses revealed that <i>M. hyopneumoniae</i> suppresses the three UPR branches and their induced apoptosis. Interestingly, while UPR activation typically drives host macrophages toward an M2 polarization phenotype, <i>M. hyopneumoniae</i> specifically obstructs this process to maintain a proinflammatory phenotype in the host macrophages. Overall, our findings propose that <i>M. hyopneumoniae</i> inhibits the host UPR to sustain macrophage survival and a proinflammatory phenotype, which may be implicated in its pathogenesis in inducing host pneumonia.