免疫檢查點（immune checkpoint）的發現，徹底改變了現代免疫學的發展方向。PD-1、CTLA-4 等免疫檢查點分子證明，免疫系統並非僅依靠活化訊號來驅動免疫反應，而是透過專門的抑制性調控機制，在病原清除、免疫耐受及組織保護之間維持精密平衡。這些發現不僅重新定義了適應性免疫（adaptive immunity）的調控模式，更開啟了癌症免疫治療的新時代。

然而，相較於適應性免疫，先天免疫（innate immunity）是否也存在類似的「免疫檢查點系統」，長期以來仍缺乏完整的概念架構。我們的研究提出一項新的觀點：NLRP12 是一個先天免疫檢查點（innate immune checkpoint），透過調控第一型干擾素（type I interferon, IFN-I）訊號的強度與持續時間，維持先天免疫系統的穩定性（immune homeostasis），並決定免疫反應最終是朝向保護性免疫（protective immunity）或病理性發炎（immunopathology）發展。此一概念將敗血症（sepsis）與全身性紅斑性狼瘡（systemic lupus erythematosus, SLE）這兩種過去被認為截然不同的疾病，整合於相同的免疫調控框架之中。

與調控 T 細胞活化的 PD-1 或 CTLA-4 不同，NLRP12 並非控制抗原專一性的免疫反應，而是位於先天免疫訊號的最上游，負責設定病原體或危險訊號所引發免疫活化的「閾值（activation threshold）」。換言之，NLRP12 並不是單純抑制發炎，而是像一個精密的「調節器（molecular rheostat）」，依據不同的發炎環境，動態調整 IFN-I 訊號的幅度，使免疫反應足以清除病原，同時避免過度放大而導致組織傷害。

我們的研究進一步發現，這個免疫檢查點具有跨疾病的一致性調控機制。在細菌感染中，Listeria monocytogenes 經由 TLR2 與 STING 路徑誘導 IFN-I 產生，進一步促進 caspase-4/11 活化、gasdermin D (GSDMD) 裂解，以及 lytic NETosis 的發生。適度的 NETosis 有助於病原清除，但當此路徑過度活化時，反而導致嗜中性白血球過早死亡、殺菌能力下降、細菌持續擴散，並加劇器官損傷及敗血症惡化。

NLRP12 正是在此過程中扮演關鍵的調控角色。正常情況下，它抑制 STING 所誘導的 IFN-I 產生，同時限制 caspase-4/11 的表現、活化及寡聚化（oligomerization），避免 NETosis 過度發生。然而，在感染初期，病原體相關分子（PAMPs）會誘導 cIAP 介導 NLRP12 的蛋白酶體降解，使免疫反應得以迅速啟動。若 NLRP12 降低過度或持續存在，則失去對 IFN-I 的制動能力，形成自我放大的正回饋迴路，最終造成失控的 lytic NETosis 與免疫功能衰竭。

令人驚訝的是，我們在 SLE 中觀察到相同的調控邏輯。不同的是，此時驅動 IFN-I 的刺激來源並非微生物，而是內源性核酸免疫複合體（nucleic acid-containing immune complexes）。慢性的 IFN-I 訊號透過 RUNX1 依賴性的表觀遺傳調控抑制 NLRP12 的轉錄，形成另一個自我增強的正回饋循環。NLRP12 的下降使單核球對核酸刺激產生過度敏感性，進一步放大 IFN-I 訊號、促進自體抗體生成、增加免疫複合體沉積及腎臟發炎，最終導致狼瘡性腎炎持續惡化。

因此，不論是病原感染或自體免疫疾病，雖然初始刺激完全不同，但最終皆匯聚於同一條共同路徑：NLRP12 檢查點失衡，導致 IFN-I 訊號失控放大，進而破壞先天免疫的恆定性。

這項發現重新定義了 IFN-I 的生物學角色。過去普遍認為 IFN-I 是一種具有雙面性的細胞激素，其保護或致病作用取決於不同疾病背景。然而，我們的研究指出，真正決定 IFN-I 生物效應的關鍵，並非 IFN-I 本身，而是控制其活化閾值的先天免疫檢查點是否完整。NLRP12 因此成為區分「適應性的 IFN-I 反應」與「病理性的 IFN-I 放大反應」的重要分子開關。

另一項重要的概念突破，是提出**免疫韌性（immune resilience）**作為先天免疫的新核心概念。傳統免疫學常認為，越強烈的發炎反應代表越有效的宿主防禦。然而，我們的研究顯示，過度活化反而會削弱免疫細胞本身的功能。在敗血症中，IFN-I 過度活化導致嗜中性白血球快速進入 lytic NETosis，不僅縮短細胞壽命，更降低殺菌能力，使感染惡化；在 SLE 中，持續的 IFN-I 訊號則使免疫系統長期處於過度警戒狀態，最終導致免疫耐受瓦解與慢性組織傷害。由此可見，真正決定疾病預後的，不是免疫反應是否夠強，而是免疫系統是否仍保有恢復平衡與適當調控的能力，而 NLRP12 正是維持此種免疫韌性的核心調節者。

此一研究亦具有重要的轉譯醫學價值。目前多數抗發炎治療著重於全面抑制免疫反應，但往往伴隨感染風險增加與免疫功能下降。我們的研究提出另一種全新的治療理念：與其全面抑制發炎，不如恢復先天免疫檢查點的正常功能，使免疫系統重新回到生理性的平衡狀態。在敗血症模式中，阻斷 IFNAR 訊號可恢復 NLRP12 的穩定性，改善嗜中性白血球存活率及殺菌能力，同時降低組織發炎；在狼瘡模式中，抑制 IFN-I 訊號亦可明顯減緩腎炎惡化。這些結果顯示，恢復 NLRP12 檢查點功能，可能比單純抑制發炎更能兼顧宿主防禦與免疫耐受。

此外，我們也證實 NLRP12 具有高度的臨床應用潛力。敗血症與敗血性休克病人的嗜中性白血球，以及 SLE 病人的周邊血單核細胞，皆呈現顯著降低的 NLRP12 表現，且與 IFN-I 訊號及疾病嚴重程度密切相關。因此，NLRP12 不僅是疾病機制中的核心調控分子，更可能成為預測疾病活性、監測治療反應及病人分層的重要生物標誌。

更重要的是，我們認為 NLRP12 並非唯一的先天免疫檢查點，而可能只是揭開此一全新研究領域的第一個代表性分子。正如 PD-1 與 CTLA-4 的發現建立了「適應性免疫檢查點」的新典範，我們提出 NLRP12 所代表的是「先天免疫檢查點（innate immune checkpoint）」的新概念。未來，更多調控模式辨識受體（pattern recognition receptors）、發炎小體（inflammasome）、核酸感知器（nucleic acid sensors）、細胞代謝及免疫細胞命運決定的負向調節分子，都可能被重新定義為先天免疫檢查點，共同形成維持免疫恆定性的調控網絡。

總結而言，我們的研究不僅揭示了 NLRP12 調控 IFN-I 訊號、嗜中性白血球命運及狼瘡發炎的新機制，更重要的是提出了一個全新的免疫學概念：先天免疫與適應性免疫一樣，同樣受到專門的免疫檢查點所調控。 NLRP12 作為第一個具有跨感染與自體免疫疾病調控能力的先天免疫檢查點，不僅建立了理解 IFN-I 相關疾病的新理論架構，也為精準免疫治療、疾病生物標誌以及未來先天免疫檢查點的發掘，開啟了一個全新的研究方向。

 

112年吳火獅醫學獎、明交大臨床醫學研究所 陳斯婷副教授

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NLRP12 Defines an Innate Immune Checkpoint that Coordinates Immune Homeostasis Across Infection and Autoimmunity

The discovery of immune checkpoints revolutionized modern immunology by demonstrating that the immune system is actively restrained through dedicated regulatory pathways rather than passive negative feedback. Molecules such as PD-1 and CTLA-4 fundamentally changed our understanding of adaptive immunity by revealing that immune tolerance, tissue protection, and effective host defense depend on precisely calibrated inhibitory mechanisms. While adaptive immune checkpoints have become central to both basic immunology and clinical medicine, whether an analogous checkpoint system exists within the innate immune compartment has remained largely unexplored. Our work identifies NLRP12 as an innate immune checkpoint that governs the magnitude, duration, and outcome of type I interferon (IFN-I)-dependent inflammation, thereby providing a conceptual framework that unifies seemingly distinct inflammatory diseases, including bacterial sepsis and systemic lupus erythematosus (SLE).

Unlike adaptive immune checkpoints, which primarily regulate antigen receptor signaling in lymphocytes, NLRP12 operates at the level of innate immune sensing. It establishes a regulatory threshold that determines whether pathogen- or damage-induced signaling produces protective immunity or progresses into pathological inflammation. This distinction is critical. Innate immunity must respond within minutes to invading microorganisms while simultaneously avoiding uncontrolled amplification initiated by microbial products or endogenous danger-associated molecular patterns (DAMPs). NLRP12 fulfills this role by functioning as a molecular rheostat that continuously calibrates IFN-I signaling according to inflammatory context, thereby preserving immune homeostasis without compromising protective immunity.

Our studies demonstrate that this checkpoint operates across remarkably different pathological settings. In bacterial infection, Listeria monocytogenes activates TLR2 and STING signaling to induce IFN-I production. IFN-I subsequently promotes caspase-4/11 activation, gasdermin D (GSDMD)-mediated membrane permeabilization, and lytic NETosis. Although controlled NET formation contributes to antimicrobial defense, excessive activation results in premature neutrophil death, impaired bacterial clearance, persistent inflammation, and severe tissue injury. NLRP12 restrains this cascade by limiting STING-mediated IFN-I production and suppressing caspase-4/11 expression, activation, and oligomerization. During infection, pathogen-derived signals induce cIAP-dependent proteasomal degradation of NLRP12, transiently releasing this checkpoint to permit early antimicrobial responses. However, sustained or excessive NLRP12 loss removes the physiological brake on IFN-I signaling, creating a feed-forward circuit that drives dysregulated lytic NETosis and immune dysfunction.

Remarkably, an analogous regulatory principle governs sterile inflammation in lupus. Instead of microbial DNA, endogenous nucleic acid-containing immune complexes chronically stimulate innate nucleic acid sensors, resulting in persistent IFN-I production. Here, IFN-I suppresses NLRP12 transcription through RUNX1-dependent epigenetic regulation, thereby reinforcing its own production and establishing a stable pathogenic feedback loop. Reduced NLRP12 expression enhances spontaneous innate immune activation, promotes monocyte hyperresponsiveness to nucleic acid stimulation, increases autoantibody production, accelerates immune complex deposition, and drives progressive lupus nephritis. Although the initiating stimuli differ dramatically between bacterial infection and autoimmune disease, both ultimately converge upon the same checkpoint pathway: disruption of NLRP12 permits uncontrolled IFN-I amplification that destabilizes innate immune homeostasis.

These findings fundamentally reshape our understanding of IFN-I biology. Type I interferons have traditionally been viewed as pleiotropic cytokines whose beneficial or detrimental effects depend largely upon disease context. Our work suggests a different interpretation. The biological consequences of IFN-I signaling are determined not simply by cytokine abundance but by the integrity of intrinsic checkpoint mechanisms that regulate signaling thresholds. NLRP12, therefore, defines a molecular switch that distinguishes adaptive IFN-I responses from pathological IFN-I amplification. Rather than functioning as a passive inhibitor, NLRP12 actively determines the transition between immune protection and immune pathology.

Equally important is the concept of immune resilience, which emerges as a unifying principle from these studies. Classical immunology often equates stronger inflammatory responses with superior host defense. Our findings challenge this paradigm by demonstrating that excessive innate immune activation compromises the functional fitness of immune cells themselves. In neutrophils, uncontrolled IFN-I signaling accelerates lytic NETosis, resulting in premature cell death, impaired bactericidal activity, persistent bacterial dissemination, and severe organ injury. Thus, hyperactivation paradoxically weakens antimicrobial immunity. In autoimmune disease, chronic IFN-I signaling similarly erodes immune resilience by maintaining continuous innate immune activation, promoting autoantibody production and irreversible tissue damage. Across both infectious and autoimmune diseases, NLRP12 preserves the capacity of innate immune cells to respond effectively without entering self-destructive inflammatory programs.

The translational implications of this checkpoint model are substantial. Current therapeutic strategies frequently attempt to suppress inflammation after pathology has already developed. However, broad immunosuppression often compromises protective immunity and increases susceptibility to infection. By contrast, restoring checkpoint function offers a fundamentally different therapeutic strategy—one that re-establishes physiological immune homeostasis rather than indiscriminately inhibiting inflammatory pathways. In experimental sepsis, IFNAR blockade interrupts the pathogenic feedback loop responsible for NLRP12 degradation, restores neutrophil survival, improves bacterial clearance, and reduces inflammatory tissue injury. Similarly, disruption of IFN-I signaling markedly attenuates lupus progression in NLRP12-deficient mouse models. These findings suggest that therapeutic restoration of the NLRP12 checkpoint may simultaneously reduce pathological inflammation while preserving essential antimicrobial defense.

Our studies also identify NLRP12 as a clinically relevant biomarker of innate immune dysfunction. Neutrophils isolated from patients with sepsis and septic shock exhibit markedly reduced NLRP12 expression, accompanied by excessive lytic NETosis and impaired bactericidal capacity. Likewise, peripheral blood mononuclear cells from SLE patients display significantly decreased NLRP12 expression that inversely correlates with IFNA expression and disease activity. These observations position NLRP12 not only as a mechanistic regulator but also as a measurable indicator of checkpoint failure in human inflammatory disease. Such biomarkers may enable patient stratification, disease monitoring, and identification of individuals most likely to benefit from therapies targeting IFN-I signaling.

Perhaps the most far-reaching implication of this work is that NLRP12 may represent only the first member of a broader family of innate immune checkpoints. Numerous inhibitory molecules regulate innate signaling pathways, yet they have generally been investigated individually rather than considered components of an organized checkpoint network. Similar to how PD-1 and CTLA-4 transformed isolated observations into the field of adaptive immune checkpoint biology, NLRP12 provides a conceptual foundation for defining an analogous regulatory architecture within innate immunity. Future studies may reveal additional checkpoint molecules governing inflammasome activation, nucleic acid sensing, pattern-recognition receptor signaling, metabolic adaptation, and inflammatory cell fate decisions. Together, these pathways could constitute an integrated innate checkpoint network responsible for maintaining immune homeostasis across diverse physiological and pathological conditions.

Collectively, our studies establish NLRP12 as a master regulator that integrates innate immune sensing, IFN-I signaling, neutrophil fate, and inflammatory homeostasis across infection and autoimmunity. More importantly, they advance a new conceptual paradigm in which innate immunity, like adaptive immunity, is governed by dedicated checkpoint mechanisms that actively preserve immune resilience. By identifying NLRP12 as an innate immune checkpoint, this work bridges fundamental immunology with translational medicine and provides a unifying framework for understanding inflammatory diseases driven by dysregulated IFN-I signaling. We anticipate that this concept will extend well beyond sepsis and lupus, offering new opportunities for biomarker development, precision immunotherapy, and the discovery of additional innate immune checkpoints that collectively maintain the delicate balance between host protection and immunopathology.

(2023 TBF Wo Ho-Su Medical Award, Associate Professor, Institute of Clinical Medicine, National Yang Ming Chiao Tung University)