Neutrophils: mediating TelOxidation and senescence

Cellular senescence is considered to be a major driver of aging, yet the mechanisms explaining the accumulation of senescent cells during life time remain unclear. In this issue, Lagnado et al (2021) show that neutrophils can trigger the senescence of neighboring cells by transmitting reactive oxygen species (ROS), which they normally produce to fight pathogens. The main genomic targets of the neutrophil‐mediated ROS damage are telomeres, supporting an intimate interplay between telomere homeostasis and oxidative stress in senescence and consequently aging.

Recent work reports a paracrine role for neutrophils in the induction of cellular senescence and tissue damage.

Chronological age is the single greatest risk factor for the development of many chronic diseases and cancers, accounting for the majority of societal morbidity, mortality, and public health costs. Recent findings indicate that both changes in cell‐autonomous and non‐autonomous processes play critical roles in aging. One such process is cellular senescence, which is triggered in response to numerous stimuli, such as telomeric DNA shortening, DNA damage, and oncogenic stresses (Gorgoulis et al, 2019). Cellular senescence is characterized by permanent cell‐cycle arrest, changes in cell morphology, chromatin structure, metabolism, gene expression and plasma membrane composition, as well as secretion of a heterogeneous panel of proinflammatory, tissue remodeling, and signaling compounds including cytokines, growth factors, and proteases (collectively named senescence‐associated secretory phenotype or SASP). The SASP molecules contribute to the functions of senescent cells in tissue repair and trigger deleterious effects if the senescent cells persist for a long time in the tissues. They also control the homeostasis of senescent cells by attracting immune cells (such as natural killer cells, macrophages, and CD4⁺ T cells) to eliminate them, by reinforcing senescent phenotypes (intracrine–autocrine senescence) or by inducing senescence (paracrine senescence). With the goal of targeting senescence to prevent and treat age‐related diseases in mind, investigations into the mechanisms explaining the accumulation of senescent cells with age are still indubitably needed.

In this issue, Lagnado et al (2021) present their discovery that innate immune cells (neutrophils) trigger the senescence of neighboring cells by transmitting reactive oxygen species (ROS), which they typically produce when they infiltrate tissues to combat various microorganisms. This illustrates the complex and seemingly antagonistic role played by the immune system in the regulation of senescent cell accumulation. When co‐cultured with neutrophils (with or without priming with lipopolysaccharide), “young” human fibroblasts enter into senescence more rapidly and with shorter telomeres compared with control cells cultured without neutrophils. Moreover, the rate of dysfunctional telomeres, characterized by their association with DNA damage response factors, increased in neutrophil‐induced senescent cells. Notably, the premature senescence and telomere damage were prevented when extracellular ROS were scavenged by adding recombinant catalase to the milieu. These results indicate that the ROS produced by the neutrophils were transmitted to the fibroblasts, where they induced telomere damage and shortening, as well as senescence. Overexpression of telomerase reverse transcriptase (TERT) in the fibroblasts rescued neutrophil‐induced senescence, which suggests that accelerated telomere shortening is the primary stressor driving senescence in the fibroblasts that are in contact with neutrophils. Nevertheless, TERT overexpression reduced neutrophil‐induced damage in DNA areas that did not colocalize with a telomeric probe. Either the ROS‐damaged extra‐telomeric DNA regions were protected by the antioxidant activity of TERT, or some damaged telomeres were too short to be detected by the probe.

Neutrophil‐induced paracrine senescence was further investigated and elegantly confirmed ex vivo using human and mouse precision‐cut liver slices and in vivo by inducing acute liver injury in mice using carbon tetrachloride. Notably, senescence and telomere damage were reverted both when mice were immunodepleted for neutrophils and when the neutrophils were engineered to overexpress catalase in their mitochondria. Furthermore, neutrophil infiltration, senescence, and telomere damage were more prominent in aging livers, and these effects were mitigated when liver cells expressing senescence markers were ablated in aging mice.

A notable finding from this article is that the main genomic target of the neutrophil‐mediated ROS damage appeared to be telomeres, which supports a wealth of data intimately connecting telomere homeostasis to oxidative stress (Barnes et al, 2019). On one hand, telomeres are particularly sensitive to oxidative stress, a process coined here TelOxidation. Telomeres shorten under oxidative stress, while antioxidant treatment can reduce this shortening (Saretzki et al, 2003). The high guanine content of telomeric DNA renders it susceptible to oxidization, leading to the accumulation of 8‐oxo‐guanine, which disrupts the binding of telomere protective factors and prevents extension by telomerase. Moreover, several antioxidant proteins are specifically associated with telomeres (Aeby et al, 2016). On the other hand, the telomere state controls mitochondrial function and ROS production. Telomere dysfunction activates p53, which binds and represses the promoters of mitochondrial biogenesis factors, leading to mitochondrial dysfunction (Sahin et al, 2011). Several telomere proteins, such as telomerase and shelterin, have additional mitochondrial functions. For instance, telomerase can have anti‐oxidative stress functions by relocating into mitochondria (Ahmed et al, 2008) and downregulation of the shelterin subunit TRF2 in skeletal muscle cells causes mitochondrial dysfunction by repressing the expression of mitochondrial sirtuin 3 (Sirt3) (Robin et al, 2020). Overall, telomeres and mitochondria, two key players in the aging process, are linked by a positive regulatory loop, in which the dysfunction of one leads to dysfunction of the other.

The results of Lagnado et al (2021) support the notion that telomere dysfunction is a primary trigger of senescence, via both developmentally programmed somatic telomere erosion and TelOxidation in response to various stresses, including neutrophil overactivation (Figure 1). They also substantiate the concept of inflammaging as a driver of senescence. Moreover, they invite us to revisit the roles of neutrophils and innate immune cells in a broader sense in aging. Neutrophils are involved in various age‐related diseases, such as rheumatoid arthritis, emphysema, atherosclerosis, chronic obstructive pulmonary disease, cancers, and acute respiratory distress syndrome, and, more recently, in the cytokine storm observed in the COVID‐19. Neutrophils are our first line of defense against bacteria and fungi, yet they can turn against integral tissues during chronic inflammation. The neutrophils of elderly people are less equipped to eradicate pathogens, since they exhibit shorter lifespans and decreased capacities for chemotaxis, phagocytosis, neutrophil extracellular trap formation, and ROS production following stimulation (Butcher et al, 2000). However, neutrophils from elderlies constitutively produce and secrete higher levels of ROS (Verschoor et al, 2015). Thus, an interesting possibility is that these neutrophils contribute to the increased number of senescent cells with age by triggering rampant TelOxidation. Neutrophils can also facilitate the metastasis of circulating cancerous cells and stimulate the awakening of dormant tumor cells within tissues (Albrengues et al, 2018; Szczerba et al, 2019). Therefore, it would be of high interest to investigate the role of neutrophil‐mediated TelOxidation in oncogenesis.

Figure 1. The neutrophil: a new player in telomere dynamics and senescence.

Erosion of telomere DNA and cellular senescence are processes that are believed to contribute to physiological and pathological aging. The rate of telomere shortening during life time can be accelerated by numerous external stressful circumstances including inflammation and oncogene activation. In this issue, Lagnado et al (2021) unveil that neutrophils, our first line of defense against various pathogens, can also contribute to an acceleration of telomere DNA shortening leading to the senescence of neighboring cells by transmitting the reactive oxygen species targeting their telomeres. This situates neutrophil at the crossroad between inflammation, telomere biology, and aging.

This report by Lagnado et al (2021) provides further evidence that reinforcing telomere protection and counteracting TelOxidation are promising strategies to prevent and treat aging‐related diseases. This could be achieved by stimulating telomerase expression or by enhancing the antioxidant and telomere capping activities of the shelterin complex.

The EMBO Journal (2021) 40: e108164.