In 2017, an estimated 48.9 million people worldwide suffered from sepsis, a life-threatening complication of severe infection (Rudd et al., 2020). Post-intensive-care syndrome is defined as new or worsening impairments in physical, cognitive, or mental health status arising after a critical illness and persisting beyond acute care hospitalization (Needham et al., 2012). Recently, increases in the incidence of sepsis and number of septic shock survivors have promoted investigation into the quality of life after sepsis (Genga and Russell, 2017). Approximately 20 % of adult male patients suffering sepsis are between the peak reproductive ages of 18–45 years (Beale et al., 2009). Several physical impairments resulting from post-intensive-care syndrome have been reported, such as pulmonary and neuromuscular problems (Johanna Josepha et al., 2022; Martín-Vicente et al., 2021), and a few reports have described reproductive dysfunction and altered gonad physiology after a critical illness (Sengupta et al., 2022, Omolaoye et al., 2022, Gacci et al., 2021). In patients with severe acute respiratory syndrome, for example as a result of SARS-coronavirus-2/COVID-19 infection, oxidative stress causes many cytokines to be overproduced, leading to a systemic cytokine storm and systemic inflammation. Germ cell apoptosis, impaired spermatogenesis, and sperm DNA fragmentation are consequences of this inflammatory response (Sengupta et al., 2022, Omolaoye et al., 2022). Oligo-crypto-azoospermia has been reported in 25 % of male patients who have recovered from COVID-19 (Gacci et al., 2021).

Interleukin (IL)-18 is a known inflammasome-mediated proinflammatory cytokine, and IL-18 levels are increased in mouse testes by inflammatory stimulation, such as lipopolysaccharide (LPS) administration (Abu Elhija et al., 2008c, Abu Elhija et al., 2008b). In addition, IL-18 is an important cytokine to maintain testicular homeostasis. IL-18 is produced by germ cells, testicular somatic cells (Leydig cells and Sertoli cells), and resident macrophages and may regulate testicular function via autocrine/paracrine signaling under physiologic conditions (Abu Elhija et al., 2008a, Abu Elhija et al., 2008d, Komsky et al., 2012, Strand et al., 2005). We previously studied the effect of endogenous IL-18 on mouse testicular germ cells apoptosis caused by E.coli LPS-induced endotoxemia in mice (Inoue et al., 2015). During the acute phase of inflammation, endogenous IL-18 induced germ cell apoptosis; whereas, IL-18 suppressed germ cell apoptosis during recovery from inflammation. We also demonstrated that LPS and high IL-18 levels induce Leydig cell apoptosis in vitro (Inoue et al., 2020). However, the impact of LPS and IL-18 on Sertoli cells remained unclear.

The primary function of Sertoli cells is to maintain and control spermatogenesis (Yamamuro et al., 2021) and to protect testicular germ cells from harmful substances by constituting the blood-testis barrier (Cheng and Mruk, 2012). Therefore, any damage to Sertoli cells could severely impact spermatogenesis (Murphy and Richburg, 2015). When considering the quality of life of patients with post-intensive-care syndrome, maintaining the function of cells that support spermatogenesis is very important to avoid male infertility. Therefore, we mimicked infectious inflammatory stimulation using LPS or IL-18 and investigated whether these stimuli induced Sertoli cell apoptosis, which may affect spermatogenesis and male fertility.