| First Author | Sun L | Year | 2019 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 316 |
| Issue | 6 | Pages | L1035-L1048 |
| PubMed ID | 30838865 | Mgi Jnum | J:275478 |
| Mgi Id | MGI:6306163 | Doi | 10.1152/ajplung.00299.2018 |
| Citation | Sun L, et al. (2019) Loss of myeloid-specific protein phosphatase 2A enhances lung injury and fibrosis and results in IL-10-dependent sensitization of epithelial cell apoptosis. Am J Physiol Lung Cell Mol Physiol 316(6):L1035-L1048 |
| abstractText | Protein phosphatase 2A (PP2A), a ubiquitously expressed Ser/Thr phosphatase is an important regulator of cytokine signaling and cell function. We previously showed that myeloid-specific deletion of PP2A (LysM(cre)PP2A(-/-)) increased mortality in a murine peritoneal sepsis model. In the current study, we assessed the role of myeloid PP2A in regulation of lung injury induced by lipopolysaccharide (LPS) or bleomycin delivered intratracheally. LysM(cre)PP2A(-/-) mice experienced increased lung injury in response to both LPS and bleomycin. LysM(cre)PP2A(-/-) mice developed more exuberant fibrosis in response to bleomycin, elevated cytokine responses, and chronic myeloid inflammation. Bone marrow-derived macrophages (BMDMs) from LysM(cre)PP2A(-/-) mice showed exaggerated inflammatory cytokine release under conditions of both M1 and M2 activation. Notably, secretion of IL-10 was elevated under all stimulation conditions, including activation of BMDMs by multiple Toll-like receptor ligands. Supernatants collected from LPS-stimulated LysM(cre)PP2A(-/-) BMDMs induced epithelial cell apoptosis in vitro but this effect was mitigated when IL-10 was also depleted from the BMDMs by crossing LysM(cre)PP2A(-/-) mice with systemic IL-10(-/-) mice (LysM(cre)PP2A(-/-) x IL-10(-/-)) or when IL-10 was neutralized. Despite these findings, IL-10 did not directly induce epithelial cell apoptosis but sensitized epithelial cells to other mediators from the BMDMs. Taken together our results demonstrate that myeloid PP2A regulates production of multiple cytokines but that its effect is most pronounced on IL-10 production. Furthermore, IL-10 sensitizes epithelial cells to apoptosis in response to myeloid-derived mediators, which likely contributes to the pathogenesis of lung injury and fibrosis in this model. |
