Sepsis, also known as systemic inflammatory response syndrome, is a potentially life-threatening condition caused by an uncontrolled inflammatory response to a microbial infection.1 This response can lead to severe tissue damage, hypotension, and organ dysfunction or failure. The septic response involves both the innate and adaptive immune systems and occurs in two distinct phases, an initial hyperinflammatory phase, followed by a period of immunoparalysis. While most patients survive the excessive cytokine production that occurs during the hyperinflammatory phase, subsequent immunoparalysis often leads to death due to an inability to eliminate either the primary infection or a secondary infection that develops.1 In both experimental animal models of sepsis and human sepsis patients, apoptotic depletion of T and B lymphocytes has been suggested to be a key mechanism leading to immunoparalysis.3, 4, 5, 6, 7 Supporting this hypothesis, several groups have shown that anti-apoptotic agents, such as caspase inhibitors and Bcl-2 overexpression, inhibit lymphocyte apoptosis and improve survival in mouse models of sepsis.8, 9, 10, 11
Anti-apoptotic cytokines that promote lymphocyte proliferation and function, such as IL-7, are also now being investigated as potential therapeutic agents for the treatment of sepsis.2, 12 IL-7 is a type I cytokine belonging to the common cytokine receptor gamma-chain (gammac) family. It plays an important role in the development, survival, proliferation, and/or activation of CD4+ and CD8+ T cells, B cells, and gamma delta T cells.13, 14 In addition, it inhibits cytokine deprivation-induced T lymphocyte apoptosis by up-regulating the anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 proteins.14, 15 These activities suggest that IL-7, like other anti-apoptotic agents, may be capable of inhibiting the immunoparalysis phase of sepsis.
A recent study by Unsinger et al. sheds more light on how IL-7 affects the septic response.15 Using a clinically relevant mouse model of sepsis, known as cecal ligation and puncture (CLP) to artificially induce intra-abdominal peritonitis and bacteremia, the authors demonstrated that injection of IL-7 inhibited the sepsis-induced apoptosis of thymocytes, and CD4+ and CD8+ T cell subsets in the spleen and mesenteric lymph nodes. This was partially attributed to an increase in Bcl-2 expression that was detected in CD4+ and CD8+ T cells following IL-7 treatment. In addition, IL-7 prevented the sepsis-induced expression of the pro-apoptotic Bim, Bmf, and Puma genes. Significantly, IL-7 treatment not only inhibited lymphocyte apoptosis, but also improved the overall survival of two different mouse strains following CLP surgery. To identify potential mechanisms by which IL-7 may improve the outcome of sepsis, the effects of IL-7 on the production of pro- and anti-inflammatory cytokines was investigated. While IL-7 did not affect the levels of TNF-alpha, IL-6, or IL-10 detected in septic mice, it did restore splenocyte production of IFN-gamma. Decreased IFN-gamma production is a hallmark of sepsis that plays a major role in its lethality, presumably due to decreased resistance to invading microorganisms, reduced macrophage activation, and loss of the delayed-type hypersensitivity (DTH) response.16 Injection of IL-7 re-established the IFN-gamma-dependent DTH response to antigenic challenge that was lacking in septic mice.15 In addition, it enhanced the expression of the leukocyte adhesion markers, LFA-1, and VLA-4 on CD4+ and CD8+ T cells in these animals, suggesting that it may improve leukocyte recruitment to the infection site. Collectively, these results indicate that IL-7 is capable of preventing several immunological defects that may contribute to septic immunoparalysis, while not affecting the severity of the hyperinflammatory response.
View Larger Image
|IL-7-induced Effects Improve the Immune Response in a Mouse Model of Sepsis. IL-7 treatment improves the immune response to sepsis by inhibiting the apoptosis of CD4+ and CD8+ T cells and promoting their expression of LFA-1 and VLA-4. Additionally, IL-7 treatment restores splenocyte production of IFN-gamma to re-establish the delayed-type hypersensitivity (DTH) response and promote the recruitment of gamma delta T cells to the infection site. IL-17 secretion by gamma delta T cells, along with mesothelial cell production of CXCL1 at the infection site, promotes neutrophil recruitment and reduces the bacterial load.|
Many of the results reported by Unsinger et al. were confirmed by Kasten et al., who also found that IL-7 treatment of septic mice led to a substantial increase in the recruitment of IL-17-secreting gamma delta T cells to the peritoneum following CLP surgery.17 Increased production of IL-17, coupled with elevated levels of CXCL1/KC, enhanced the early recruitment of neutrophils to the infection site, although it did not affect their activation or function. Enhanced neutrophil recruitment led to a reduction in bacterial load 24 hours following CLP surgery, without causing a significant increase in tissue damage. Together, these findings support the conclusion that IL-7, in addition to promoting T lymphocyte proliferation and function, may also improve survival in septic mice by promoting neutrophil recruitment to the infection site, thereby enhancing the innate immune response.
This symbol denotes references that cite the use of R&D Systems products.