Basophils beyond allergic and parasitic diseases

Abstract

Basophils bind IgE via FcεRI-αβγ_2, which they uniquely share only with mast cells. In doing so, they can rapidly release mediators that are hallmark of allergic disease. This fundamental similarity, along with some morphological features shared by the two cell types, has long brought into question the biological significance that basophils mediate beyond that of mast cells. Unlike mast cells, which mature and reside in tissues, basophils are released into circulation from the bone marrow (constituting 1% of leukocytes), only to infiltrate tissues under specific inflammatory conditions. Evidence is emerging that basophils mediate non-redundant roles in allergic disease and, unsuspectingly, are implicated in a variety of other pathologies [e.g., myocardial infarction, autoimmunity, chronic obstructive pulmonary disease, fibrosis, cancer, etc.]. Recent findings strengthen the notion that these cells mediate protection from parasitic infections, whereas related studies implicate basophils promoting wound healing. Central to these functions is the substantial evidence that human and mouse basophils are increasingly implicated as important sources of IL-4 and IL-13. Nonetheless, much remains unclear regarding the role of basophils in pathology vs. homeostasis. In this review, we discuss the dichotomous (protective and/or harmful) roles of basophils in a wide spectrum of non-allergic disorders.

Keywords: COVID-19, myocardial infarction; alarmins; allergy; autoimmunity; basophil; cancer.

Figure 1

Proposed mechanism by which basophils influence the inflammatory response to promote wound healing and tissue repair following myocardial infarction (MI). MI is caused by the rupture of an atherosclerotic plaque causing the occlusion of a coronary artery, which then results in cardiac tissue damage due to ischemia (90). It has been shown in mice that several immune cells [e.g., monocytes/macrophages, neutrophils, dendritic cells (DCs), B and T cells, and natural killer (NK) cells, basophils and eosinophils infiltrate the heart after experimental MI (70, 97, 110). For basophils, this infiltration into the heart is evident 3 days following MI and peaks 7 days after the MI event (70). Monocytes/macrophages represent the most prevalent immune cells after MI. Cardiac resident macrophages contribute to the initial neutrophil infiltration into the ischemic area (111). Resident macrophages are reduced in murine models 1 day post-infarction (112). Within 1-3 days infiltrating bone marrow- and spleen-derived Ly6C^hi monocytes are recruited into the injured cardiac tissue and differentiate to Ly6C^low macrophages facilitating clearance of necrotic cardiomyocytes. At approximately 5-7 days post MI, macrophages adopt a reparative phenotype, contributing to the resolution of inflammation and fibrotic tissue formation (70). By day 3, infiltrating basophils into the injured cardiac tissue release IL-4 and IL-13, which induce phenotypical and functional changes within macrophages expressing anti-inflammatory and tissue repair genes (70). Formation of neovessels in the healing infarct play an important role in repairing the infarcted myocardium (113). Basophils (114), macrophages (–117), and cardiac mast cells (118, 119), are major sources of angiogenic factors. Collectively, results in mice models of MI indicate that basophils infiltrating infarcted heart promote resolution of cardiac inflammation and scar formation.

Figure 2

Kidney and wild-type mice subjected to unilateral ureter obstruction (UUO) surgery revealed the presence of neutrophils, monocytes/macrophages, dendritic cells (DCs), and basophils (71). Injured proximal tubular cells (PTs) in UUO kidney express Il34, Cxcl10, and the key profibrotic factor (71), platelet derived growth factor subunit B (PDGFB). PDGFB released by injured tubular activates the PDGFB receptor (PDGFBR) on fibroblasts to release TGF-β. Profibrotic PT cells participate in the recruitment of myeloid and lymphoid cells and the local fibroblast activation. CXCL1 released from PT cells induces the recruitment of basophils through the engagement of CXCR2. Basophils in UUO kidney can be activated by IL-33 and IL-18 released from the stroma to secrete IL-6. This cytokine favors T_H17 differentiation from CD4⁺ T cells in UUO kidneys. IL-17A and TGF-β released from T_H17 cells contribute to renal fibrosis. IL-4 and IL-13 released from activated basophils can contribute to macrophage activation (–130). PDGF released from injured PT cells activates the PDGFR on myofibroblasts causing the release of TGF-β. Macrophages are also a major source of IL-6. Collectively, these findings indicate that basophils and their mediators contribute to kidney fibrosis.

Figure 3

Basophils can promote tumor progression through different mechanisms. Galectin-3 (Gal-3) is a lectin expressed by several cancer cells (137), including the A549 adenocarcinoma cell line (EC-Gal-3). Gal-3 activates human basophils to release IL-4 and IL-13 (16, 136), which are widely known to promote M2-like macrophages, the major players in the TME (–130). IL-4⁺ basophils have been found in the TME of human and experimental pancreatic cancer (72). Human and mouse basophils also secrete VEGF-A and angiopoietin 2 (ANGPT2) that can promote tumor angiogenesis (, –148). Basophils can promote IL-6 and IL-8 release from epithelial cell lines through a mechanism requiring cell-to-cell contact (149) (JTS, unpublished). Tumor cell-derived IL-6/IL-8 play a critical role in metastasis formation (150). Dendritic cells and monocytes activated by EC-Gal-3 release TNF-α and IL-6 in vitro (151). These cytokines, combined with M2 cell-derived IL-10 and TGF-β induce T-cell exhaustion by up-regulating checkpoint inhibitors (i.e., PD-1), which interact with tumor cell-associated PD-L1 to decrease cytotoxic T cell activity (152, 153). These results suggest that basophils can promote tumorigenesis in certain experimental and clinical conditions. Adapted from Poto et al. (74).

Figure 4

Basophils can promote tumor suppression through different mechanisms. Vascular endothelial growth factors (VEGFs) released by tumor and immune cells in the TME (e.g., macrophages, mast cells) (–159) induce basophil recruitment via the activation of VEGFR2 on these cells (155). IL-3, released from intratumoral lymphocytes, mast cells and tumor cells (10, 160, 161), is the major growth, differentiation, priming and activating factor for both human and mouse basophils via the activation of the IL-3 receptor (IL-3Rα/CD123) (–10). Intratumoral basophils secrete CCL3 and CCL4 which favor CD8⁺ T cell infiltration in TME, favoring melanoma rejection in mice (75). IL-33 produced by epithelial and tumor cells, plays a critical role in tumorigenesis (162) by upregulating granzyme B mRNA and the surface expression of CD63 in basophils. Mouse basophils activated by IL-33 cause melanoma cell death in vitro (142). Mouse (104, 163) and, in certain conditions, human basophils (164, 165) release TNF-α and granzyme B (142, 166), which exerts cytotoxic activity on cancer cells (102, 167). Tumor resident basophils overexpressing CD123, CCR3, CD63, CD203c mRNAs are associated with improved outcome in ovarian cancer (88, 154). These findings indicate that, under specific experimental and clinical circumstances, basophils can play an anti-tumorigenic role. Adapted from Poto et al. (74).

Figure 5

Proposed mechanism linking IgE basophils to autoimmunity in systemic lupus erythematosus (SLE). Serum IgE levels are increased in SLE and correlate with severe disease manifestations (, –175). IgE against several autoantigens have been reported in SLE (, , –182). Basophils from SLE patients show an activated phenotype in overexpressing CD203c (76), the prostaglandin D₂ (PGD₂) receptor [chemoattractant receptor-homologous molecule (CRTH2) expressed on Th2 cells], and CXCR4, the receptor for CXCL12 (185). Once recruited to the secondary lymphoid organs, activated basophils release IL-4, which drives B cell isotype switching toward IgE and autoreactive IgE (177, 181). Dendritic cells (DCs) in lymph nodes also act on B cells, triggering their differentiation into plasma cells and potentiating the formation of self-reactive autoantibodies (186). IgE immune complexes contribute to basophil activation. Deposits of IgG and IgE autoantibodies in the kidney play a major role in lupus nephritis.

Figure 6

Hypothetical mechanisms by which dysregulated epithelial cells and inflammatory signaling by lamina propria immune cells in response to microbiota, contribute to inflammatory bowel disease (IBD) pathogenesis. Intestinal epithelial cells separate the lamina propria and deeper tissues from the luminal environment containing the intestinal microbiota (239). Increased intestinal permeability can potentiate immune-mediated systemic and intestinal inflammation in IBD (240). Damaged epithelial cells release alarmins (IL-33, TSLP, and IL-25) (115, 123, 241), which then regulate underlying immune cells (242), including basophils (9), macrophages (157), and DCs (243). Macrophages can damage epithelial cells directly by TNF-α secretion. Basophils accumulate in inflamed IBD compared to non-inflamed mucosa and to colon of healthy controls (125). Activated T cells infiltrate inflamed colons and release IL-3 which can contribute to the attraction and/or survival of basophils locally (238). Specific components of gut microbiota induce the emergence of intestinal T_H17 cells. Basophils may also promote T_H17 responses (125). Activated T cells release IL-23, which converts homeostatic T_H17 cells to pathogenic T_H17 cells, and play a major role in Crohn’s disease (244).