Mechanisms underlying the impact of interleukin family on acute kidney injury: Pathogenesis, progression, and therapy

Background

Acute kidney injury (AKI) is a severe renal disorder affecting approximately 10%–15% of hospitalized patients and up to 50% in intensive care units (ICUs). Its pathogenesis involves complex inflammatory regulatory mechanisms. As core components of the cytokine network, interleukins (ILs) exert pleiotropic effects in AKI development, extensively participating in inflammation, fibrosis, tissue injury repair, and remote organ damage. During AKI progression, distinct IL members execute diverse biological effects through unique signaling pathways. Pro-inflammatory ILs such as IL-1α, IL-1β, IL-12, IL-17A, and IL-18 exacerbate AKI, while protective ILs including IL-2, IL-10, IL-13, IL-27, and IL-37 mitigate injury. Certain ILs, such as IL-4, IL-6, IL-9, IL-11, IL-22, and IL-33, exhibit dual roles.
Emerging therapeutic strategies targeting ILs or their receptors—particularly monoclonal antibodies and extracellular vesicle technology—show significant promise. Consequently, understanding these mechanisms is critical for developing innovative therapies and improving outcomes in AKI patients.

Origins and Structure of Interleukins (ILs)‌

The interleukin (ILs) family is primarily produced by T cells, B cells, macrophages, dendritic cells, endothelial cells, and epithelial cells. Most ILs are small polypeptides or glycoproteins with molecular weights ranging from ‌15-30 kDa‌‌. Although amino acid sequences vary significantly across different ILs, members within the same family frequently exhibit ‌conserved sequence regions. Critically, the structure of ILs is intrinsically linked to their function–their unique ‌spatial conformation‌ and ‌structural domains‌ empower them to execute diverse biological roles within the immune system (Figure 1)‌.

‌Mechanisms of ILs in AKI‌

Mechanisms underlying the exacerbation of AKI progression. IL-1α and IL-1β exacerbate inflammation and tissue damage in diverse AKI models (e.g., cisplatin-induced, ischemic) by activating the ‌nuclear factor κB (NF-κB) pathway.IL-8 (CXCL8) recruits neutrophils through ‌CXCR1/2 receptors‌, promoting inflammatory responses, tubular cell damage, senescence, and fibrosis‌. Elevated plasma IL-8 levels serve as a biomarker for predicting severe AKI‌.IL-12 aggravates AKI by enhancing ‌dendritic cell maturation‌ and amplifying the release of multiple inflammatory mediators‌.IL-17A worsens injury in sepsis-associated and cisplatin-induced AKI by increasing pro-inflammatory cytokines, inducing ‌neutrophil infiltration‌, and triggering tubular cell apoptosis‌. It further promotes subsequent renal fibrosis‌.IL-18 is significantly elevated in the urine of AKI patients, serving as a reliable early biomarker‌. It exacerbates sepsis-, nephrotoxic-, and ischemia-reperfusion-induced AKI by amplifying ‌inflammatory cascades‌‌.IL-36α contributes to AKI pathogenesis through NF-κB pathway activation and upregulation of IL-6/TNF-α (Figure 2)‌.‌

Mechanisms underlying the inhibition of AKI progression. Low-dose IL-2 protects against ischemia-reperfusion-induced renal damage. Treatment with ‌IL-2/anti-IL-2 antibody complexes (IL-2C)‌ or ‌IL-2/IL-33 fusion protein (IL-233)‌ significantly attenuates ischemia-reperfusion injury (IRI) and nephrotoxic AKI, improving renal function while reducing cellular apoptosis and oxidative stress. IL-10 mediates anti-inflammatory and immunomodulatory responses through ‌JAK/STAT pathway activation‌.IL-15 enhances survival signaling in renal tubular epithelial cells via ‌JAK/STAT and PI3K/Akt pathways‌, mitigating cisplatin-induced apoptosis.The nephroprotective effect of IL-17E (IL-25) involves ‌enhanced type 2 innate lymphoid cell (ILC2s) activity‌, promotion of M2 macrophage polarization, and suppression of M1 macrophages.Additionally, IL-13, IL-27, IL-35, IL-37, and IL-38 demonstrate anti-inflammatory potential and renal protective properties (Figure 3).

The dual mechanisms of action of ILs in AKI. IL-4 primarily exerts biological effects through activation of ‌JAK-STAT and PI3K/Akt/mTOR pathways‌. It facilitates ‌M2 macrophage polarization‌ to accelerate renal tubular repair, demonstrating protective effects in IRI-AKI models, yet concurrently drives renal fibrotic progression.IL-6 activates ‌STAT3 via classical and trans-signaling pathways‌, participating in anti-inflammatory responses. Paradoxically, IL-6 deficiency improves renal function and reduces inflammatory infiltration in both IRI and HgCl₂-induced AKI models, indicating its pro-inflammatory role in AKI progression.IL-33 activates immunity through the ‌ST2/MyD88 pathway‌, while also exhibiting renoprotective effects via promotion of ‌ILC2s, M2 macrophages, Tregs, and Th2 responses‌. Its net effect depends on dosage, duration, and molecular conformation.Additionally, ‌IL-9 and IL-11‌ demonstrate context-dependent dual modulation in AKI (Figure 4).

‌During the pathological transition from AKI to CKD, the role of ILs shifts from acute injury response towards chronic fibrotic remodeling.‌ IL-1β can induce renal tubular epithelial cell senescence and pro-fibrotic factor release in hypoxic microenvironments. IL-18 exacerbates fibrosis by promoting inflammatory infiltration and M2 macrophage transformation. Conversely, IL-10 can suppress inflammation and M1 polarization, while IL-22 antagonizes TGF-β1-induced fibrosis by activating Jagged1/Notch1 signaling. The pro-fibrotic effects of ILs play a crucial driving role in AKI-CKD progression.

‌Therapeutic Potential of ILs in AKI‌

Targeted therapies based on ILs signaling pathways have emerged as novel strategies for AKI intervention. The IL-1 family fusion protein Rilonacept (neutralizing IL-1α/β) and IL-17A/C neutralizing antibodies can effectively alleviate inflammatory responses. IL-18 inhibitors simultaneously reduce renal tubular apoptosis and delay fibrosis, while IL-22 modulation specifically alleviates cisplatin-induced nephrotoxicity. Additionally, IL-33 monoclonal antibodies can prevent cardiac injury following AKI. Compared to interventions targeting ILs, therapies targeting ILs receptors may offer greater advantages by blocking multiple pathogenic ligands (e.g., IL-1α/β) and comprehensively terminating downstream signaling pathways. Furthermore, engineered extracellular vesicle (EV) technology has opened new avenues: IL-10-containing EVs enhance IL-10 targeting and reduce the risk of AKI-to-CKD progression, while IL-37-encapsulated neutrophil membrane vesicles (N-MVs) significantly improve renal ischemia-reperfusion injury by promoting angiogenesis and exerting anti-inflammatory effects. These advances highlight the considerable therapeutic potential of targeting ILs for AKI treatment (Table1).

‌Future Perspectives‌

The authors comprehensively elaborate on the diversity and complexity of ILs' roles in AKI pathogenesis. The review also describes how ILs coordinate immune cell activation and mediate crosstalk between these cells and renal parenchymal cells, establishing a balance between pro-inflammatory/anti-inflammatory responses and injury/repair processes. ILs-based targeted therapeutic strategies (e.g., specifically targeting particular ILs or their receptors) and emerging EV technologies demonstrate significant potential for AKI treatment.

Sources: https://spj.science.org/doi/10.34133/research.0738