The Role of Treg-expressed Mmp12 During the Resolution of Acute Lung Injury 2111

Description Foxp3+ regulatory cells (Tregs) are vital in facilitating the resolution of lung injury through anti-inflammatory and pro-repair mechanisms. Prior Mock lab work demonstrated that Tregs isolated from the lung during LPS-induced acute lung injury (ALI) have a twenty-fold increase in expression of the transcript, Mmp12, compared to baseline pulonmary Tregs. Using the Cre-lox system, we generated a new strain of mice with a deletion in Mmp12 only in Tregs (Mmp12ΔTreg). Lungs from wild-type mice (WT) and Mmp12ΔTreg mice were collected at a resolving timepoint in two ALI models: LPS (day 7) and mouse-adapted strain of influenza PR8 (day 15). There was no distinct phenotype with the parameters of lung injury in the Mmp12ΔTreg mice compared to their parent strain in either of our injury models. However, at LPS resolution, the Mmp12ΔTreg mice had increased numbers of neutrophils and B cells compared to the WT; in our influenza model, we also see increased numbers of neutrophils at resolution. TAILS proteomic analysis on the BALs at LPS resolution highlights several proteins with neo-N-terminal enriched in the wild type, but NOT the Mmp12ΔTreg mice. Pathway analysis based on protein cleavage shows differences in inflammatory pathways between the two strains. The effect of Mmp12 deficient Tregs results in changes in immune kinetics during ALI. Ongoing efforts are further identifying Treg Mmp12-specific effects that impact the lung microenvironment during resolution. Funding Sources NHLBI supported research: R01HL152077. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)