Increased neutrophil senescence is associated with impaired immunosuppressive activity in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a complex pathogenesis that was previously thought to involve primarily adaptive immunity. Emerging evidence underscores the role of neutrophils in shaping immune dysregulation and inducing organ damage in lupus. This study aims to investigate the dynamics of neutrophil senescence and its relationship with lupus, an area that remains poorly understood. Here, we identify a significantly elevated proportion of CXCR4hiCD62Llo senescence-like neutrophils in the peripheral blood of SLE patients compare to that in the healthy donors. Increased numbers of senescence-like neutrophils are positively correlated with SLE disease activity and autoantibody production in SLE patients. In addition, senescence-like neutrophils derived from SLE patients exhibit an impaired ability to suppress the proinflammatory activity of natural killer (NK) cells and CD4+ T cells. Further mechanistic exploration suggests that these senescence-like neutrophils might exert their immunosuppressive effects via reactive oxygen species (ROS) production under physiological conditions. Our results demonstrate that senescence-like neutrophils could serve as biomarkers for assessing the disease activity of SLE. The compromised immunosuppressive function of senescence-like neutrophils provides a new perspective on SLE pathophysiology and may pave the way for the development of novel therapies.

1. Introduction

Systemic lupus erythematosus (SLE) is a representative autoimmune disorder characterized by a complex pathogenesis and the involvement of multiple organ systems [1]. Therefore, investigating the pathogenesis of SLE is of paramount importance, as it offers a theoretical foundation for the development of targeted therapeutics.

Neutrophils are among the earliest cells in human peripheral blood that respond to microbial invasion [2]. Studies have indicated that neutrophils in patients with lupus present abnormal functions, marked by a diminished capacity for recognizing and clearing apoptotic neutrophils mediated by C1q, calreticulin, and CD91 [3]. Additionally, lupus neutrophils show an enhanced ability to form neutrophil extracellular traps (NETs), which contain substantial amounts of chromatin, double-stranded DNA, and autoantigens, such as granular proteins [4]. Moreover, neutrophils in lupus are subject to ferroptosis, and specific inhibitors of ferroptosis significantly alleviate the severity of the disease in lupus-susceptible mice [5]. These findings imply that neutrophils might play a facilitating role in the pathogenesis of lupus. However, we previously discovered that the elimination of neutrophils at an early stage in a lupus mouse model led to an exacerbation of autoimmunity, further revealing that neutrophils inhibit the IFN-γ response via reactive oxygen species (ROS) production. Both type I interferons and type II interferons (IFNs) are implicated in the pathogenesis of SLE [6]. Neutrophils may play a bidirectional regulatory role in the onset and progression of lupus.

Although neutrophils are typically considered a relatively homogeneous population, emerging evidence indicates the existence of heterogeneity. Under steady-state circumstances, neutrophil heterogeneity might arise from aging and the replenishment of freshly released neutrophils from the bone marrow. As neutrophils age, they gradually lose CD62L expression and upregulate CXCR4 level [7]. These senescence-like neutrophils constitute an overly active subset that enhances the activation of αMβ2 integrin (Mac-1) and increases the formation of NETs under inflammatory conditions. The pro-inflammatory activity of neutrophils is positively correlated with their aging in circulation. The morphology of senescence-like neutrophils is characterized by pronounced nuclear hypersegmentation [8]. However, another subset of mature human neutrophils (CD62LdimCD16bri) presenting hypersegmented nuclear morphology has been identified as a distinct circulating population of myeloid cells with the capacity to suppress human T-cell proliferation [9]. Given their overlapping and contradictory natures, the functions of senescence-like neutrophils need to be further investigated. Furthermore, the mechanism of senescence-like neutrophils in the pathogenesis of SLE has rarely been reported. This study aimed to investigate the dynamics of neutrophil senescence and its relationship with lupus.