A novel IL-18-mediated anti-bacterial circuit to enforce intestinal host defence and immunity

Together with inflammatory IL-1b, IL-18 is a well-known effector cytokine when inflammasome is activated in myeloid cells such as macrophages. While increased IL-18 levels in serum and mucosal biopsies are correlated to inflammatory Crohn’s disease, it remains largely unexplored whether and how epithelium-derived IL-18 contributes to barrier function.

Here we show that IL-18 is a bona fide IL-22-related gate keeper for epithelial barrier. IL-22, a protective cytokine for the epithelium, coordinates with IL-18 for an early host defense against Crohn’s adherent-invasive E coli (AIEC), via induction of stem cell-mediated epithelial regeneration and Paneth cell-directed anti-microbial peptides (AMP). IL-22 induces phospho-Stat3 binding to the Il-18 promoter in gut epithelial cells and additively promotes crypt immunity with IL-18. In organoid culture, IL-18 robustly promotes organoid budding and induces Lgr5⁺ stem cells in a Stat3-independent but Akt-Tcf4 dependent manner. During AIEC infection, injection of IL-18 corrected compromised T-cell IFNg production and restored Lysozyme⁺ Paneth cells in IL-22-deficient mice, but IL-22 injection failed to do so in IL-18-deficient mice, thereby placing IL-22-Stat3 signalling upstream of the IL-18 mediated barrier defence function.

In summary, IL-22-Stat3 signaling initiates an IL-18 response circuit for host defense at the frontline barrier: an IL-18-Stat3 signaling to boost Paneth cells for anti-microbial response, an IL-18-Akt-Tcf4 signaling to promote Lgr5⁺ stem cells for tissue repair, and an IL-18/IL-12 signaling to promote IFNg⁺ T cells for AIEC clearance.  

強化腸道防禦及免疫力, 由細胞激素IL-18主導的新穎抗菌迴路

與發炎性細胞激素IL-1b 一樣, IL-18 是當骨髓細胞 (如巨噬細胞) 內的發炎體活化時, 產生的一個具效應的細胞激素。雖然IL-18在血清及黏膜檢體中的增高與發炎性腸道克隆氏症有關聯, 但由表皮細胞大量產生的 IL-18 是否對腸壁的屏障功能有調節作用仍不清楚。

我們的研究首度揭示, IL-18 是一個如假包換的, 並與 IL-22 相關的腸壁屏障守護者。在克隆氏症的黏附侵入型大腸桿菌感染過程中, 保護型的 IL-22 能協調 IL-18, 藉由調控幹細胞的再生修復, 與刺激潘氏細胞產生抗菌物質, 來提高宿主的早期防禦力。在腸道表皮細胞中, IL-2 2能誘導磷酸化的 Stat3 結合到 IL-18 啟動子, 並與 IL-18 一同增強腸道免疫力。利用腸道類器官培育, 我們發現 IL-18 能透過 Akt-Tcf4 的機轉 ,來誘導類器官萌芽而促進腸道幹細胞發育。在大腸桿菌感染的過程中, 施打 IL-18 到 IL-22 基因剃除鼠, 能挽救腸道喪失的 T 細胞 IFNg 反應及抗菌的潘氏細胞功能。相反的, 施打 IL-22 到 IL-18 基因剃除鼠, 卻沒有相同的功效。因此確立了 IL-22-Stat3 的免疫機轉是位於 IL-18 上游。

總結來說, 在大腸桿菌感染的早期, 我們發現 IL-22-Stat3 的信息傳遞, 在第一線的腸道表皮細胞, 可引發一個 IL-18 的反應迴路。此腸道抗菌迴路包含了由 IL-18-Stat3 來增強潘氏細胞的抗菌功能, 由 IL-18-Akt-Tcf4 的信息傳遞來增強幹細胞的組織修復, 由 IL-18/IL-12 的信息傳遞來增強T細胞的 IFNg 反應。