Role of Basophils in a Broad Spectrum of Disorders

Abstract

Basophils are the rarest granulocytes and have long been overlooked in immunological research due to their rarity and similarities with tissue-resident mast cells. In the last two decades, non-redundant functions of basophils have been clarified or implicated in a broad spectrum of immune responses, particularly by virtue of the development of novel analytical tools for basophils. Basophils infiltrate inflamed tissues of patients with various disorders, even though they circulate in the bloodstream under homeostatic conditions. Depletion of basophils results in the amelioration or exaggeration of inflammation, depending on models of disease, indicating basophils can play either beneficial or deleterious roles in a context-dependent manner. In this review, we summarize the recent findings of basophil pathophysiology under various conditions in mice and humans, including allergy, autoimmunity, tumors, tissue repair, fibrosis, and COVID-19. Further mechanistic studies on basophil biology could lead to the identification of novel biomarkers or therapeutic targets in a broad range of diseases.

Keywords: COVID-19; IL-4; allergy; autoimmune diseases; basophils; fibrosis; tissue repair; tumor.

Figure 1

Role of basophils in the pathogenesis of atopic dermatitis. Basophils contribute to allergic inflammation, pruritus, barrier dysfunction and Staphylococcus aureus colonization in atopic dermatitis (AD). 1) Basophil-derived interleukin (IL)-4 stimulates group 2 innate lymphoid cells (ILC2s) to enhance the production of IL-5 and CCL11, leading to enhanced recruitment of eosinophils to the skin lesion (upper left panel). Basophil-derived IL-4 also augments the differentiation of naïve T cells into Th2 cells in draining lymph nodes (upper right panel). 2) Basophil-derived leukotriene C4 (LTC4) acts on CysLTR2⁺ sensory neurons, inducing acute itch flares in AD (lower left panel). 3) Basophil-derived IL-4 promotes proliferation and differentiation of keratinocyte (lower middle panel). 4) Basophil-derived IL-4 suppresses the IL-1 and IL-23 production by keratinocytes, leading to reduced production of IL-17A by γδ T cells and, therefore, increased susceptibility to S. aureus infection (lower right panel).

Figure 2

Role of basophils in tissue repair responses, tissue fibrosis and emphysema formation. 1) In skin allergy, basophil-derived interleukin (IL)-4 promotes the differentiation of inflammatory monocytes into anti-inflammatory M2 macrophages, leading to the resolution of allergic inflammation. In the liver infected with Listeria monocytogenes, basophil-derived IL-4 promotes monocyte differentiation into M2 macrophages which replace damaged Kupffer cells, promoting healing of liver damage. In myocardial infarction, basophil-derived IL-4 and/or IL-13 promotes the generation of reparative Ly6C^lo macrophages which enhances post-infarction tissue repair. 2) In allograft heart transplantation, basophil-derived IL-4 promotes tissue fibrosis, possibly by acting on tissue-resident macrophages or fibroblasts, leading to the generation of myofibroblasts and deposition of collagen fibers. 3) In a chronic obstructive lung disease (COPD) model, basophil-derived IL-4 promotes the generation of MMP-12⁺ interstitial macrophages which promote the destruction of alveolar walls and emphysema formation.

Figure 3

Feedback loop for the exacerbation of systemic lupus erythematosus. In the mouse model of systemic lupus erythematosus (SLE) and in patients with SLE, autoreactive IgE antibodies can be detected in the blood. Autoreactive IgE antibodies form immune complexes with corresponding autoantigens and activate blood-circulating basophils. Activated basophils upregulate the surface expression of CD62L and CXCR4 and infiltrate into lymph nodes. They produce interleukin (IL)-4, IL-13, and B cell-activating factor (BAFF) which in turn induces autoantibody production from B cells, resulting in the deposit of immune complexes in the kidney and in disease progression.