Upregulation of IL-33 protects against chronic allograft rejection

Abstract Background IL-33 is a broadly expressed, but poorly understood IL-1 cytokine. After lung and muscle injury, immunoregulatory and tissue reparative functions of IL-33 have been suggested. Yet, pro-inflammatory IL-33 properties are known. How endogenous IL-33 shapes outcomes after of solid organs transplant is an important, but unanswered question. Methods Mouse heterotopic heart transplant (HTx) models of both acute [BALB/c (H2d) to WT or Il33−/− B6 (H2b)] and chronic rejection [Il33+/+ or Il33−/− bm12 (H2bm12) to WT or Il33−/− B6 mice] were utilized. Cytokines were quantitated in transplant and naïve heart tissues by qRT-PCR and Western blot. HTx were evaluated microscopically following staining with H&E, Trichrome or IHC. IL-33+ cell types within the HTx were identified by confocal. Splenocytes were analyzed by flow cytometry. IL-33 quantities were determined in clinical samples from pediatric HTx (n=39) recipients. Results Acute and chronic rejection, and surgery increased HTx IL-33 levels in mice. BALB/c IL-33+HTx cells were predominantly CD45− cTnI− vimentin+ with subsets of α-SMA+ Desmin+ or CD31+ cells. Clinical samples displayed increases in IL-33 during acute rejection. IL-33 was protective during both acute and chronic rejection in mice. At 100 days post HTx, Il33−/− Bm12 grafts displayed dramatically increased chronic rejection-associated fibrosis and vessel disease, especially in Il33−/−recipients. A lack of IL-33 was associated with increased HTx immune infiltrates as well as decreased systemic and local Treg levels. Conclusion Our data support an unappreciated, yet critical role for upregulated IL-33 in heart allograft protection, particularly during alloimmune responses causing chronic rejection.