Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

Abstract

Atopic individuals show enhanced type 2 immune cell responses and a susceptibility to infections with certain bacteria and viruses. Although patients with allergic diseases harbor normal counts of circulating neutrophils, these cells exert deficient effector functions. However, the underlying mechanism of this dysregulation of neutrophils remains ill defined. Here, we find that development, aging, and elimination of neutrophils are accelerated in mice with a predisposition to type 2 immunity, which, in turn, causes susceptibility to infection with several bacteria. Neutrophil-mediated immunity to bacterial infection was greatly decreased in mice with a genetic or induced bias to type 2 immunity. Abrogation of interleukin-4 (IL-4) receptor signaling in these animals fully restored their antibacterial defense, which largely depended on Ly6G+neutrophils. IL-4 signals accelerated the maturation of neutrophils in the bone marrow and caused their rapid release to the circulation and periphery. IL-4–stimulated neutrophils aged more rapidly in the periphery, as evidenced by their phenotypic and functional changes, including their decreased phagocytosis of bacterial particles. Moreover, neutrophils from type 2 immune predisposed mice were eliminated at a higher rate by apoptosis and phagocytosis by macrophages and dendritic cells. Collectively, IL-4 signaling–mediated neutrophil aging constitutes an important adaptive deficiency in type 2 inflammation, contributing to recurrent bacterial infections.

Mechanisms regulating neutrophil responses in immunity, allergy, and autoimmunity

“…Previous descriptions of neutrophil aging included gradual loss of granularity, phagocytic capacity and release of NETs, and increased aptitude for ROS production 82 . Interestingly, neutrophils in “atopic” mice with a predisposition to type 2 immune responses exhibited an aged phenotype, reduced phagocytic activity, and increased rate of apoptosis 69 . In line with an increased rate of apoptosis, neutrophils in atopic mice were readily phagocytosed by macrophages and DCs in bone marrow and spleen.…”

“…82 Interestingly, neutrophils in "atopic" mice with a predisposition to type 2 immune responses exhibited an aged phenotype, reduced phagocytic activity, and increased rate of apoptosis. 69 In line with an increased rate of apoptosis, neutrophils in atopic mice were 3). 116 Biologic agents targeting the IL-1 family of cytokines have shown clinical success in autoinflammatory diseases, 117 underlining the central role of these cytokines in the pathology.…”

“…Very recently, using a mouse model of atopy, IL‐4R signals were demonstrated to accelerate maturation of neutrophils in the bone marrow and aging of circulating neutrophils 69 . Previous descriptions of neutrophil aging included gradual loss of granularity, phagocytic capacity and release of NETs, and increased aptitude for ROS production 82 .…”

“…| REGULATION OF NEUTROPHILSSimilar to patients with numerical or functional neutrophil deficiencies, neutropenic mice show significant defects to control infections, such as with murine cytomegalovirus68 and Listeria monocytogenes (L. monocytogenes) 69. However, in other instances, neutrophils may do more harm than good.…”

Neutrophils in aging and aging‐related pathologies

“…It was shown that IL‐4 signaling triggered aging of neutrophils, which were then eliminated at higher rates through macrophage phagocytosis. Accelerated aging and efferocytosis of neutrophil in type 2 inflammation led to increased susceptibility to bacterial infections 98 …”