Project Grant F31HL182245

IL-5 ACTS AS A PLEIOTROPIC CYTOKINE, SIGNALING TO MULTIPLE DIFFERENT CELL TYPES TO CONVERGE ON PROMOTING SURVIVAL IN ACUTE LUNG INJURY - PROJECT SUMMARY/ABSTRACT ACUTE LUNG INJURY (ALI) IS A COMMON COMPLICATION FOLLOWING TRAUMA TO THE HEART POST-SURGERY, POST-CARDIAC ARREST, AND CAN OCCUR FOR MANY OTHER REASONS, SUCH AS LUNG INFECTION OR SEPSIS. PREVIOUS WORK FROM OUR LAB ESTABLISHED THAT ILC2-DERIVED IL-5 PROMOTES SURVIVAL DURING BLEOMYCIN (BLEO)-INDUCED ALI. IL-5 IS A CRITICAL CYTOKINE FOR EOSINOPHILS, AND THIS PATHWAY IS A SUCCESSFUL DRUG TARGET OF EOSINOPHIL-DRIVEN DISEASES SUCH AS EOSINOPHILIC ASTHMA. WHILE ANTI-IL-5 THERAPEUTICS SUCCESSFULLY LIMIT EOSINOPHILIC ASTHMA SYMPTOMS IN CHILDREN, THESE CHILDREN STILL EXPERIENCE ASTHMATIC EXACERBATIONS. DURING BLEO-INDUCED ALI, TREATMENT WITH IL-5 NOT ONLY INCREASED SURVIVAL, BUT ALSO REDUCED RED BLOOD CELLS IN THE AIRWAY AND LESS PULMONARY EDEMA. IF IL-5 IS BENEFICIAL IN SOME CONTEXTS, BUT NEUTRALIZING IL-5 SIGNALING IS NOT ENTIRELY EFFECTIVE AGAINST EOSINOPHIL-DRIVEN DISEASES, IT IS IMPORTANT TO DISSECT THE PROTECTIVE ROLES OF IL-5 SIGNALING ARE DURING ALI. WE FOUND THAT EOSINOPHIL-DEFICIENT MICE HAD NO DIFFERENCE IN SURVIVAL FROM BLEO-INDUCED ALI COMPARED TO CONTROLS, SUGGESTING AN EOSINOPHIL INDEPENDENT ROLE FOR IL-5RA. AT HOMEOSTASIS, ILC2-DERIVED IL-5 SUPPORTS B-1 CELL DEVELOPMENT IN BODY CAVITIES AND THE LUNG. FURTHER, MY CO-SPONSOR, DR. STUREK HAS SHOWN THAT THE B-1 SUBSET IS RECRUITED TO THE AIRWAYS AND LUNG PARENCHYMA, WHERE THEY PROTECT AGAINST ALI, IN PART THROUGH NATURAL ANTIBODY (NAB) PRODUCTION. HOWEVER, WHETHER IL-5 PROTECTS AGAINST ALI THROUGH THE EXPANSION AND ACTIVATION OF B-1 CELLS REMAINS UNKNOWN. THUS, MY OVERALL HYPOTHESIS IS THAT DURING BLEO-INDUCED ALI, IL-5 PROMOTE SURVIVAL IN ACUTE LUNG INJURY VIA B-1 CELLS. TO ADDRESS THIS HYPOTHESIS, WE HAVE GENERATED A NOVEL MOUSE MODEL ALLOWING FOR THE SELECTIVE DEPLETION OF IL-5RA USING THE CRE-LOX SYSTEM. THE LONG-TERM GOAL OF THIS STUDY IS TO DISSECT THE PROTECTIVE ROLES OF B CELLS AND IL-5 SIGNALING DURING ALI. TO ACHIEVE THESE GOALS, I PROPOSE THE FOLLOWING AIMS. AIM 1: DETERMINE THE ROLE OF IL-5RA+ B CELLS DURING IL-5- INDUCED PROTECTION FROM ALI. I HYPOTHESIZE THAT IL-5 SIGNALING DURING ALI INCREASES IL-5RA+ B CELLS WHICH ARE PROTECTIVE. AIM 2: DETERMINE IF IL-5 SIGNALING INFLUENCES SPECIFICITY OF B CELL ANTIBODIES DURING ALI. I HYPOTHESIZE THAT EXOGENOUS IL-5 TREATMENT OR ENDOGENOUS IL-5 DURING ALI SERVES AS THE SIGNAL FOR B CELLS TO PRODUCE MORE OSE-SPECIFIC ANTIBODIES. IMPACT: THIS WORK WILL BOTH UNRAVEL HOW IL-5 SIGNALING PROTECTS DURING ACUTE LUNG INJURY AND FURTHER EXPLORE THE EFFECT IL-5 EXCLUSIVELY ON B CELLS. THESE STUDIES COULD POTENTIALLY REVEAL A NEW THERAPEUTIC USE FOR IL-5. ADDITIONALLY, THE TECHNIQUES PROPOSED, THE EXPERIMENTAL PLANNING AND SET-UP, THE MENTORSHIP OPPORTUNITIES, AND THE PLANNED MANUSCRIPTS, CONFERENCE PRESENTATIONS AND NETWORKING WILL PREPARE ME FOR A FUTURE CAREER AS AN ACADEMIC PRINCIPAL INVESTIGATOR.