Beyond fibrosis: Emerging role of IL-11 in regulating innate and adaptive immune cell plasticity

Interleukin-11 (IL-11), a member of the IL-6 cytokine family, is well-recognized for its role in driving fibrosis and stromal remodeling. Extensive research on this fibroblast-associated cytokine have focused on its roles in tissue scarring and extracellular matrix deposition. However, emerging evidence has unveiled its sophisticated role in immunomodulation, extending far beyond its conventional pro-fibrotic functions. This review demonstrates how IL-11 influences phenotypic shifts of immune cell plasticity within both innate and adaptive compartments. In the myeloid lineage, IL-11 orchestrates macrophage polarization and macrophage-to-mesenchymal transition (MMT), regulates neutrophil extracellular traps (NETs) formation, and modulates the plasticity of NK cells, while in the lymphoid compartment, it influences T helper cell differentiation, regulatory T cell stability, and B cell responses. Of note, the effect of IL-11 on immune cells may be exerted either directly through engagement with the target cells or indirectly via intercellular crosstalk. Furthermore, we also highlight the therapeutic potential of modulating the IL-11 signaling axis through monoclonal antibodies, siRNAs, peptides, recombinant proteins, and small molecules to restore immune homeostasis across multiple disease states.