PMID- 30838865 OWN - NLM STAT- MEDLINE DCOM- 20200324 LR - 20201210 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 316 IP - 6 DP - 2019 Jun 1 TI - Loss of myeloid-specific protein phosphatase 2A enhances lung injury and fibrosis and results in IL-10-dependent sensitization of epithelial cell apoptosis. PG - L1035-L1048 LID - 10.1152/ajplung.00299.2018 [doi] AB - 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. FAU - Sun, Lei AU - Sun L AD - Department of Pediatrics and Critical Care, University of Michigan , Ann Arbor, Michigan. FAU - Hult, Elissa M AU - Hult EM AD - Molecular and Integrative Physiology Graduate Program, University of Michigan , Ann Arbor, Michigan. FAU - Cornell, Timothy T AU - Cornell TT AD - Department of Pediatrics and Critical Care, University of Michigan , Ann Arbor, Michigan. FAU - Kim, Kevin K AU - Kim KK AD - Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan. FAU - Shanley, Thomas P AU - Shanley TP AD - Department of Pediatrics, Northwestern University Feinberg School of Medicine and Stanley Manne Children's Research Institute at Lurie Children's Hospital , Chicago, Illinois. FAU - Wilke, Carol A AU - Wilke CA AD - Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan. FAU - Agarwal, Manisha AU - Agarwal M AD - Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan. FAU - Gurczynski, Stephen J AU - Gurczynski SJ AD - Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan. FAU - Moore, Bethany B AU - Moore BB AD - Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan. AD - Department of Microbiology and Immunology, University of Michigan , Ann Arbor, Michigan. FAU - Dahmer, Mary K AU - Dahmer MK AUID- ORCID: 0000-0001-7329-1943 AD - Department of Pediatrics and Critical Care, University of Michigan , Ann Arbor, Michigan. LA - eng GR - R01 HL108904/HL/NHLBI NIH HHS/United States GR - R35 HL144481/HL/NHLBI NIH HHS/United States GR - T32 AI007413/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190306 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (IL10 protein, mouse) RN - 0 (Lipopolysaccharides) RN - 11056-06-7 (Bleomycin) RN - 130068-27-8 (Interleukin-10) RN - EC 3.1.3.16 (Protein Phosphatase 2) SB - IM MH - Animals MH - Apoptosis/genetics MH - Bleomycin/toxicity MH - Cells, Cultured MH - Disease Models, Animal MH - Epithelial Cells/*metabolism MH - Interleukin-10/*metabolism MH - Lipopolysaccharides/toxicity MH - Lung Injury/chemically induced/genetics/*pathology MH - Macrophages/immunology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Protein Phosphatase 2/*genetics MH - Pulmonary Fibrosis/chemically induced/genetics/*pathology MH - Respiratory Distress Syndrome/pathology PMC - PMC6620666 OTO - NOTNLM OT - ARDS OT - acute lung injury OT - acute respiratory distress syndrome OT - fibroproliferation OT - macrophage COIS- No conflicts of interest, financial or otherwise, are declared by the authors. EDAT- 2019/03/07 06:00 MHDA- 2020/03/25 06:00 PMCR- 2020/06/01 CRDT- 2019/03/07 06:00 PHST- 2019/03/07 06:00 [pubmed] PHST- 2020/03/25 06:00 [medline] PHST- 2019/03/07 06:00 [entrez] PHST- 2020/06/01 00:00 [pmc-release] AID - L-00299-2018 [pii] AID - 10.1152/ajplung.00299.2018 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2019 Jun 1;316(6):L1035-L1048. doi: 10.1152/ajplung.00299.2018. Epub 2019 Mar 6.