Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets

Abstract

The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33. Recent advancements in therapeutic strategies, specifically the utilization of biologics targeting pivotal cytokines (IL-4, IL-5, and IL-13), are discussed, offering insights into both challenges and opportunities. Acknowledging the pivotal role of innate type-2 cytokines in orchestrating immune responses positions them as promising therapeutic targets. The evolving landscape of research and development in this field not only propels immunological knowledge forward but also holds the promise of more effective treatments in the future.

Keywords: ILC2; Interleukin-25; Interleukin-33; Natural killer T-cells; TSLP; Type-2 cytokines.

Figure 1. Type-2 immunity is initiated by epithelial cell-derived alarmins that then provoke the release of other type-2 cytokines by innate cells.

When epithelial cells are damaged or triggered by allergens, viruses, or parasites, they produce the alarmins IL-25, IL-33, and/or TSLP. These cytokines can be considered to be a subset of innate type-2 cytokines. IL-25 is released in a disulfide-linked homodimeric form that is inactive until it is cleaved by MMP7. The cleaved IL-25 then binds to the IL-25R heterodimer (IL-17RA and IL-17RB), which is constitutively expressed on ILC2s and iNKT cells. This binding event induces these cells to secrete IL-13. The ILC2s also produce IL-5. IL-5 and IL-13 are classical innate type-2 cytokines. With regard to IL-33, it is normally sequestered in the epithelial-cell nucleus in its immature full-length form. When the epithelial cells are activated, they release the immature protein into the extracellular space, where it undergoes proteolytic cleavage into mature IL-33 fragments. These fragments bind to the heterodimeric ST2 receptor (IL-1RAcP and ST2L) on macrophages, ILCs, mast cells, basophils, eosinophils, and Th2 cells. These cells then secrete classical type-2 cytokines. With regard to TSLP, it is expressed as long-form (lfTSLP) and short-form (sfTSLP) isoforms. Both bind to the TSLP heterocomplex (IL-7Rα and TSLPR), which is expressed by mast cells, ILC2s, macrophages, basophils, and DCs. sfTSLP is thought to act as a homeostatic immune decoy. lfTSLP promotes type-2 cytokine production by directly activating innate-immune cells. In the case of DCs, lfTSLP increases their expression of costimulatory molecules and promotes DC activation of type-2 cytokine-producing CD4⁺ T cells.

Figure 2. Effects of innate type-2 cytokines in protective and pathogenic immune responses.

(A) Helminth infections often lead to tissue damage and the release of alarmins such as IL-25 and IL-33 by the necrotic cells. The alarmins bind to local innate-immune cells such as ILC2s, which prompts them to rapidly produce classical type-2 cytokines such as IL-5 and IL-13. IL-5 induces mast cells to degranulate; the released proteases then damage the helminths. IL-5 also induces eosinophilia, which is crucial for controlling parasitic infections, while IL-13 promotes eosinophil recruitment to the infected site. IL-33 also initiates goblet-cell hyperplasia in the lung and intestine, thereby creating an unfavorable environment for helminths. (B) Allergens damage epithelial cells and induce them to release the alarmins IL-25 and IL-33. These directly activate ILC2s and iNKT cells, which release type-2 cytokines and thereby trigger allergic reactions such as asthma and atopic dermatitis. For example, IL-5 and IL-13 induce eosinophilia and local eosinophil recruitment, respectively. IL-13 also generates goblet-cell hyperplasia in the lung, thereby inducing the mucus overproduction that characterizes allergic diseases. (C) Fibrosis is mediated by IL-13/IL-4-secreting ILC2s and iNKT cells. These cytokines directly induce fibroblasts to differentiate into myofibroblasts, which produce vast amounts of collagen and fibronectin. They also potently contract the extracellular matrix. Both activities result in stiffly remodeled tissue that is a hallmark of fibrosis and interferes with normal tissue functions. IL-4 from ILC2s/iNKT cells also activates macrophages and induces eosinophil recruitment. These effects further promote myofibroblast differentiation. (D) Adipose-tissue metabolism is driven by macrophages. Alternatively-activated (M2) macrophages promote adipocyte browning, which releases energy in the form of heat. The differentiation of adipose-tissue M2 macrophages is initiated by hormones, exercise, and environmental stimuli such as cold, which induce the release of the alarmins IL-25 and IL-33 in adipose tissue. These alarmins activate local ILC2s, iNKT cells, and type-II NKT cells, which secrete IL-5 and IL-13. IL-5 induces eosinophilia and IL-13 recruits these cells into the adipose tissue. The eosinophils produce IL-4, which converts the resident macrophages into M2 macrophages that release mediators that promote adipocyte browning. When the innate immune cell-eosinophil-M2 macrophage axis is disrupted, classically-activated macrophages (M1) predominate and the adipocytes accumulate fat and induce obesity.