Early Events Triggering the Initiation of a Type 2 Immune Response

Abstract

Type 2 immune responses are typically associated with protection against helminth infections and also with harmful inflammation in response to allergens. Recent advances have revealed that type 2 immunity also contributes to sterile inflammation, cancer, and microbial infections. However, the early events that initiate type 2 immune responses remain poorly defined. New insights reveal major contributions from danger-associated molecular patterns (DAMPs) in the initiation of type 2 immune responses. In this review, we examine the molecules released by the host and pathogens and the role they play in mediating the initiation of mammalian innate type 2 immune responses under a variety of conditions.

Keywords: DAMPs; allergens; cancer; helminths; sterile inflammation.

Figure 1.. Helminths and Allergens Initiating Type 2 Immune Responses.

The schematic illustrates multiple often nonoverlapping pathways that together trigger type 2 immune responses in mice. DAMPs, such as extracellular ATP released from damaged cells, and the release of preformed IL-33, activate ILC2s and myeloid cells resulting in type 2 cytokine production, alternatively activated (M2) macrophages, and development of type 2 responses. Efferocytosis of neutrophils can also contribute to M2 macrophage activation [39]. Furthermore, damaged and dying cells secrete uric acid which binds and activates DCs, to initiate the type 2 immune response [125]. TGF-β released from protease damaged cells stimulates the production of IL-5 and IL-13 from ILC2s [126]. At early stages of infection, tuft cell chemosensing of larvae triggers the production of cysLTs, which activate ILC2s in the presence of constitutive IL-25 production by tuft cells [120]. Activated ILC2s produce IL-13, in turn leading to tuft cell hyperplasia and associated increases in IL-25 [116,118,119]. TFF2 secreted by epithelial cells stimulates the release of IL-33 and stimulates CD4⁺ T cells to produce IL-4 and IL-13 [16]. Stimulation of epithelial cells by IL-13 also induces the production of intelectin which in turn increases the production of alarmins IL-25, IL-33, and TSLP. Although not shown, recent studies also suggest that IL-17 and type I interferons also contribute to the initiation of type 2 immunity [24,25,28]. Abbreviations: cysLT, cysteinyl leukotriene; DAMP, danger-associated molecular pattern; DC, dendritic cell; IL, interleukin; ILC2, group 2 innate lymphoid cell; N2, alternative activated neutrophil; NMU, neuromedin U; TFF2, trefoil factor 2; TSLP, thymic stromal lymphopoietin; TGF-β, transforming growth factor-β.

Figure 2.. Signaling Molecules Initiating Type 2 Immune Response in Sterile Inflammation.

Microparticles, trauma, and tissue injury can trigger sterile inflammatory responses including innate type 2 immunity. In mouse models of liver injury, ATP recruitment of GATA-6⁺ macrophages and the activation via hyaluronan–CD44 can lead toM2 macrophage phenotype polarization [69]. Microparticles induce Syk and downstream BTK-1 signaling leading to the release of IL-33 in mice [62]. Silica has also been shown to prime type 2 immune responses by triggering the release of DNA by damaged cells, thereby activating the cGAS/STING pathway and increased IFN-I in mice [68]. Type 2 immunity is also mediated by activation of p38 MAPK and PLA₂, resulting in the release of arachidonic acid from membrane lipids. Arachidonic acid leads to the production of COX2 and mPGES-1, converting arachidonic acid to PGE₂, which can enhance IgE production in mice [54]. Abbreviations: BTK-1, Bruton’s tyrosine kinase-1; cGAS, cyclic GMP-AMP synthase; COX2, cyclooxygenase-2; IFN-I, interferon-I; MAPK, mitogen-activated protein kinase; mPGES-1, membrane-associated PGE synthase-1; MSU, monosodium urate crystal; Mtb, Mycobacterium tuberculosis; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PLA₂, phospholipase A2; STING, stimulator of interferon genes; Syk, spleen tyrosine kinase.

Figure 3.. The Tumor Microenvironment Can Suppress Immune Responses by Initiating Type 2 Immunity.

Tumor cell secretion of PGD₂ stimulates CRTH2 signaling on ILC2s and their consequent IL-13 production and recruitment of MDSCs in mice [106,107]. Secreted CSF-1 can promote the differentiation of alternative activated (M2) macrophages, while CCL2 secreted from tumor and stromal cells and eosinophil secretion of IL-13 can promote M2 macrophage recruitment [95]. VEGF-A secreted by these M2 macrophages can lead to extravasation of tumor cells and metastasis in certain models [–97]. Mouse M2 macrophage release of CCL7 can lead to the recruitment and activation of IL-4-producing basophils, in turn activating Th2 CD4⁺ T cells to produce IL-4/IL-13 [110]. Furthermore, tumor-derived CSF-2 can activate N2 TANs and PD-L1 expression can suppress T cell function in certain APL and bladder cancer human patients [104]. Tumor derived SCF can also drive the production of ROS from TANs, leading to suppression of T cell function in mice [105]. Abbreviations: CCL, C-C motif chemokine ligand; CCR2, C-C chemokine receptor type 2; CRTH2, chemoattractant receptor-homologous molecule 2; CSF, colony-stimulating factor; CSF-1R, CSF-1 receptor; DC, dendritic cell; ILC2, group 2 innate lymphoid cell; M2 TAM, M2 tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; N2 TAN, N2 tumor-associated neutrophil; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PGD2, prostaglandin D2; ROS, reactive oxygen species; SCF, stem cell factor; Th2, T helper type 2; TME, tumor-microenvironment; VEGF-A, vascular endothelial growth factor A.