Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Abstract

SummaryThe structurally and functionally related interleukin‐4 (IL‐4) and IL‐13 cytokines play pivotal roles in shaping immune activity. The IL‐4/IL‐13 axis is best known for its critical role in T helper 2 (Th2) cell‐mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL‐4 and IL‐13 stimulate a wide range of innate and adaptive immune cells, as well as non‐hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL‐4/IL‐13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL‐4/IL‐13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL‐4 and IL‐13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL‐4/IL‐13 biology and enabling researchers to exploit these insights to develop effective interventions.

Intestinal microflora promotes Th2-mediated immunity through NLRP3 in damp and heat environments

“…IL-4 can be produced by activated CD4 + T cells, CD4 + NK1.1 + natural killer T (NKT) cells, group 2 innate lymphoid cells (ILC2s), macrophages, eosinophils, basophils, and mast cells. IL-4 plays a significant role in regulating immune activity and is crucial for the development of Th2-mediated responses ( 43 ). Previous studies have found that NLRP3 protein can activate Th2 cells ( 44 ) through IL-4 and promote M2 macrophage polarization ( 45 ).…”

Functionally Relevant Cytokine/Receptor Axes in Myelofibrosis

“…The receptor chains lack endogenous kinase activity and thus utilize receptor-associated kinases, such as the Janus family tyrosine kinases (JAKs) and others, for signal transduction. The main signaling pathways activated by IL-13Rα1 and IL-4Rα chain heterodimerization are the JAK/STAT pathway, the IRS pathway, and the SHP-1/SHP-2/SHIP pathway [ 99 ]. Among them, STAT6 is the major transcription factor pathway activated in response to IL-4 and IL-13 binding, and STAT6 phosphorylation is crucial for the expression of IL-4 and IL-13 target genes [ 98 , 99 , 100 , 101 , 102 ].…”

“…The main signaling pathways activated by IL-13Rα1 and IL-4Rα chain heterodimerization are the JAK/STAT pathway, the IRS pathway, and the SHP-1/SHP-2/SHIP pathway [ 99 ]. Among them, STAT6 is the major transcription factor pathway activated in response to IL-4 and IL-13 binding, and STAT6 phosphorylation is crucial for the expression of IL-4 and IL-13 target genes [ 98 , 99 , 100 , 101 , 102 ]. The IRS-2/PI3K/AKT/mTOR pathway contributes additional transcriptional modulation mainly through AKT-dependent activation of FoxO1, Bad, TOR, and NF-κB.…”

“…The IRS-2/PI3K/AKT/mTOR pathway contributes additional transcriptional modulation mainly through AKT-dependent activation of FoxO1, Bad, TOR, and NF-κB. The Src Homology 2 domain-Containing Phosphatase (SHP)-1, SHP-2 or SH2 Domain–Containing 5′-Inositol Phosphatase (SHIP) pathway is haematopoietically restricted, serving as a phosphatase system to dampen IL-4 and IL-13 signaling [ 99 ].…”

Interleukin-13 (IL-13)—A Pleiotropic Cytokine Involved in Wound Healing and Fibrosis

“…The proinflammatory cytokine IL-13, which was identified in 1989, has a very broad spectrum of action. A recent review [ 16 ] explains the importance and function of IL-13 for the regulation of immunoglobulins (Ig), inflammation, anti-parasitic reactions, fibrogenesis, and allergic reactions. IL-13 can also be released as a preform by granulocytes such as basophils, mast cells, or eosinophils, a process in which IgE plays an important role [ 16 , 17 ].…”