INTERLEUKIN33 IS CRITICAL FOR CONTROLLING TISSUE OXIDATIVE STRESS AND AGING THROUGH REGULATION OF DISPOSAL OF UNWANTED CELLS

Background: Abnormal disposal of unwanted cells or substances generates reactive oxygen species (ROS), which accelerate tissue aging. We previously discovered consecutive expression of interleukin33 (IL33) in many tissues (1). We aimed to determine if IL33 was involved in disposal of unwanted cells or tissue wastes. Methodology: Tissue aging process in Il33-/- mice was compared to those in wild or Il33+/- mice (2). We focused on ovaries, because 99% of follicles/oocytes are discarded during atresia (3). Results: Il33-/- mice showed impaired disposal of atretic follicles/oocytes, leading to accumulation of massive ROS and elevation of oxidative stress (OS) in ovaries. Thus, Il33-/- female showed an accelerated decline in oocyte reservoir at young ages and much shorter reproductive lifespan. Further study revealed a cascade for how IL33 regulated disposal of unwanted cells. First, unwanted cells signal the endothelia of surrounding vein to release IL33. Second, IL33 recruits MHC-II+ macrophages into the tissues. Third, invading macrophages induce autophagy in the unwanted cells followed by invasion of scavenger macrophages, which cleanup minimally left cell debris; disposal of unwanted follicles/oocytes was completed. In addition, deletion of IL33 gene was associated with decreased autophagy activities in CNS. Conclusion: IL33 regulates a mechanism for disposal of unwanted cells or tissue wastes to eliminate tissue OS.