The IL-17 family is emerging as an important regulator of inflammatory response and has become a key to expanding the understanding of cytokine networks that coordinate innate and adaptive immunity . The role of the IL-17A signaling pathway in sepsis is still a research hotspot. Roark CL et al.  showed that bacteremia significantly increased 6h after the establishment of the non-severe CLP sepsis model in IL-17R knockout mice administered with neutralizing IL-17A. Flierl et al.  gave anti-IL-17A immediately after establishing a mouse model of severe CLP sepsis, and the 7-day survival rate of the mice increased to 58% (n = 13, P < 0.05) compared with the 8% survival rate of the control mice treated with IgG, demonstrating that in the severe CLP model (the 7-day mortality rate was 100%), Neutralizing IL-17A successfully reduced mortality in mice. JB Li et al.  analyzed that in the severe CLP sepsis model, increased IL-17A produced by γδT cells induces neutrophil recruitment and promotes the inflammatory response, and subsequent studies proved that abundant IL-17A in the peritoneal cavity plays a key role in the intense and sustained inflammatory response of severe sepsis. Neutralizing IL-17A in the peritoneum has a protective effect on organ tissue damage and death caused by sepsis. Therefore, we speculate that the difference between these studies is due to the different severity of sepsis models used.
Acute lung injury (ALI) is one of the early manifestations of sepsis, and its pathogenesis is still not completely clear. Some scholars believe that the destruction of the alveolar epithelium caused by sepsis is its pathophysiological basis . Qinchuan Li et al. demonstrated a close correlation between increased IL-17 levels in LPS-induced ALI mice and the severity of ALI. Overproduction of IL-17 promoted the development of ALI, while IL-17 deficient mice were resistant to ALI induction. Mechanistically, IL-17 regulates lung inflammation in LPS-induced ALI mice . Pulmonary edema is one of the typical symptoms of acute lung injury caused by sepsis  and is usually attributed to the loss of alveolar-capillary barrier structure . The degree of pulmonary edema was evaluated by examining the W/D weight ratio of lung tissue in rats. Our results showed that the W/D weight ratio of lung tissue in rats with sepsis was significantly reduced by the neutralization of IL-17A, as well as the content of inflammatory factors such as IL-6 and TNF-α. This is consistent with our lung histopathological results, suggesting that ScUCiumab can reduce alveolar epithelial cell edema and inflammatory exudation in the alveolar cavity of rats with severe sepsis.
Monin L et al.  suggested that il-17A could bind and interact with nuclear factor κB factor activator 1(Act1) after binding with IL-17RA. Act1 rapidly recruits and ubiquitizes TNF receptor-associated factor 6 (TRAF6), which triggers NFκB activation [22, 23]. NFκB, one of the most important nuclear factors in cells, encodes many pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, and is involved in the gene expression of sepsis-induced inflammation and the pathophysiological process of ALI, playing a central role in regulating the inflammatory response [24, 25]. Inhibition of the NFκB signaling pathway has previously been shown to play a protective role in sepsis . Therefore, blocking the NFκB signaling pathway can reduce the inflammatory response and lung injury in CLP-induced ALI mice. In this study, we found that the expression of p-NFκB p65 and p-IKBα was significantly inhibited by the neutralization of IL-17A in the lung tissues of septic rats, and the expression of downstream genes IL-6, TNF-α, IL-1β, and IFN-γ was decreased by the neutralization of IL-17A. Based on these results, secukinumab may play a role in the treatment of acute lung injury associated with sepsis by inhibiting the activation of the IKBα/NFκB pathway and thereby inhibiting the release of related inflammatory factors.
In addition to lung tissue, numerous studies have demonstrated that IL-17A levels are elevated during multiple organ injuries caused by sepsis. Experimental and clinical data of CJ Luo et al.  showed the importance of IL-17A secretion in AKI, suggesting that IL-17A is associated with increased levels of pro-inflammatory cytokines in AKI and accelerated apoptosis of renal tubular epithelial cells. In addition, IL-17A can serve as a chemokine to recruit neutrophils to the kidney . IL-17A is also upregulated in animal models of acute renal tubular injury and cisplatin-induced AKI . The role of IL-17A has also been found in intestinal barrier dysfunction caused by sepsis. IL-17A-mediated inflammation disrupts intestinal epithelial barrier function, increases intestinal permeability, and leads to intestinal bacterial translocation by inhibiting intestinal cell proliferation and inducing its apoptosis [30, 31]. This is consistent with the results of our study. When dissecting septic rats, we found through naked eye observation that the intestinal tract of septic rats was dilated and edema, with severe adhesion, and a large amount of purulent fluid could be seen in the intestinal tract. Previous studies have shown that neutralizing IL-17A protects intestinal barrier integrity, reduces systemic inflammation and bacterial transmission, and reduces mortality in septic mouse models . In addition, other experiments have shown that IL-17A levels are significantly increased in myocardial ischemia-reperfusion injury, inflammation, and apoptosis .
It is worth mentioning that although many previous studies have investigated the role of IL-17A in sepsis by neutralizing IL-17A with anti-IL-17A antibodies. However, our study is the first to demonstrate the protective effect of neutralizing IL-17A in rats with severe sepsis using an approved monoclonal antibody drug, Secukinumab.
There is increasing evidence that IL-17A is involved in the pathophysiology of sepsis, involving the regulation of inflammation and immune responses. Correspondingly, elevated IL-17A levels were associated with disease severity of sepsis, suggesting that IL-17A could serve as a potential biomarker for assessing prognosis in clinical settings. In addition, the development of IL-17A as a therapeutic target must be situational, taking into account the fact that IL-17A may be protective or pathogenic. Future work will need to further explore the pathophysiological mechanisms by which IL-17A interferes with different immune responses during sepsis.