A Novel Hybrid Cytokine IL233 Mediates regeneration following Doxorubicin-Induced Nephrotoxic Injury

Abstract

Kidney injury, whether due to ischemic insults or chemotherapeutic agents, is exacerbated by inflammation, whereas Tregs are protective. We recently showed that IL-2 and IL-33, especially as a hybrid cytokine (IL233 - bearing IL-2 and IL-33 activities in one molecule), potentiated Tregs and group 2 innate lymphoid cells (ILC2) to prevent renal injury. Recent studies have indicated a reparative function for Tregs and ILC2. Here, using doxorubicin-induced nephrotoxic renal injury model, we investigated whether IL233 administration either before, late or very late after renal injury can restore kidney structure and function. We found that IL233 treatment even 2-weeks post-doxorubicin completely restored kidney function accompanied with an increase Treg and ILC2 in lymphoid and renal compartments, augmented anti-inflammatory cytokines and attenuated proinflammatory cytokine levels. IL233 treated mice had reduced inflammation, kidney injury (Score values - saline: 3.34 ± 0.334; IL233 pre: 0.42 ± 0.162; IL233 24 hrs: 1.34 ± 0.43; IL233 1 week: 1.2 ± 0.41; IL233 2 week: 0.47 ± 0.37; IL233 24 hrs + PC61: 3.5 ± 0.74) and fibrosis in all treatment regimen as compared to saline controls. Importantly, mice treated with IL233 displayed a reparative program in the kidneys, as evidenced by increased expression of genes for renal progenitor-cells and nephron segments. Our findings present the first evidence of an immunoregulatory cytokine, IL233, which could be a potent therapeutic strategy that augments Treg and ILC2 to not only inhibit renal injury, but also promote regeneration.

Emerging Roles of Interleukin-33-responsive Kidney Group 2 Innate Lymphoid Cells in Acute Kidney Injury

“…Administration of soluble ST2 (sST2; 100 µg/day, on days 1, 2, and 3 of cisplatin administration) decreased the levels of SCr, acute tubular necrosis, and tubular apoptosis [20]. The dose of IL-33 used in this study was higher than that used in other recent studies [48][49][50][51]. It is not clear if the detrimental effect of exogenous IL-33 observed in this study resulted from the excessive immune response elicited by IL-33.…”

“…Several studies have reported the pathological roles of IL-33 in renal IRI [53], cisplatin-induced AKI [20], and ovalbumin-induced nephrotoxicity models [56]. Additionally, some recent studies have demonstrated that IL-33-mediated immune responses contribute to renal protection in the mouse AKI models [48][49][50][51]. The IL-33/ST2 signaling pathway may function as a double-edged sword and is involved in both the pathological and tissue reparative processes by affecting various cell types at different phases of disease progression [18].…”

“…Recently, Sharma et al combined IL-2 and IL-33 for fine-tuning the immunomodulatory effects of IL-33 on Tregs and ILC2s [51]. The hybrid IL-2-IL-33 (IL233) fusion protein exhibited promising therapeutic efficacy in various mouse models of kidney injuries, including IRI [51], doxorubicin-induced nephrotoxicity [50], lupus nephritis [65], and diabetic nephropathy [66]. These studies indicated that the IL233 fusion protein could be a novel immunomodulatory cytokine that regulates multiple nephropathic factors with potential renoprotective applications.…”

“…Although the IL-33 protein levels are upregulated in the kidneys after AKI, the kidney-resident ILC2s are not accumulated or expanded unless exogenous IL-33 was systemically administered [48][49][50][51]. This potentially implied that the endogenous IL-33 may not be sufficient to elicit the expansion of kidney ILC2s.…”

“…However, IL-33 also promotes anti-inflammatory responses to suppress the inflammation via alternatively activated macrophages (AAMs), myeloid-derived suppressive cells (MDSCs), and regulatory T-cells (Tregs) [46,47]. Recent studies have also demonstrated that IL-33-mediated immune responses are involved in renal protection using mouse AKI models [48][49][50][51]. The growth factors, such as amphiregulin (AREG) derived from IL-33-responsive group 2 innate lymphoid cells (ILC2s) or Tregs, are reported to promote epithelium regeneration after tissue injury [52].…”