Introduction Inflammasomes are large cytosolic protein compl

Introduction Inflammasomes are large cytosolic protein complexes with multiple components that trigger a rapid immune response against pathogen-associated molecular pattern Tadalafil (PAMPs) during pathogen infections or damage-associated molecular pattern molecules (DAMPs) during tissue damage [1]. Activation of inflammasome leads to pyroptosis, which is a proinflammatory form of regulated cell death initiated by the activation of CASP1/caspase-1 or CASP11/caspase-11 [2]. Although the type and number of inflammasomes are growing, the NLRP3 (NLR family pyrin domain containing 3) inflammasome is the most extensively studied form of inflammasome. The core components of NLRP3 inflammasome is composed of three proteins: NLRP3, PYCARD (PYD and CARD domain containing, also termed ASC), and CASP1. Adenosine triphosphate (ATP), the intracellular energy-carrying molecule and an extracellular DAMP, was the first reported inducer of NLRP3 inflammasome activation [3]. Subsequently, a wide array of stimuli including PAMPs and DAMPs were identified to activate the NLRP3 inflammasome in various cells, especially in macrophages. The pathologic role of the NLRP3 inflammasome in inflammatory and infectious disease has been well documented [4], but the regulation mechanisms and signaling pathways of its activation remain largely unknown [5]. ALK (anaplastic lymphoma kinase) is a tyrosine kinase receptor for pleiotrophin, a growth factor involved in development, inflammation, and immunity [[6], [7], [8], [9]]. Aberrant ALK activity resulting from gene changes (e.g., point mutation, gene amplification, chromosomal translocation, and DNA rearrangement) has been involved in the development of certain human cancers (e.g., non-small-cell lung cancer and anaplastic large cell lymphomas) [10]. Various ALK fusion proteins are constitutively active in cancer cells, contributing to cell proliferation and drug resistance [10]. ALK inhibitors such as ceritinib (the secondary-generation ALK inhibitor) and lorlatinib (the third-generation ALK inhibitor) have been approved for targeted therapy for patients with lung cancer [11]. In addition to playing an oncogenic role in tumorigenesis, ALK exhibits an immunological role in innate immunity and tumor immunity [[12], [13], [14]]. In particular, ALK-mediated TMEM173 (transmembrane protein 173, also termed STING) activation in macrophages and monocytes has been implicated in the pathogenesis of sepsis caused by infection [12].
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Discussion Inflammation is not only a defense mechanism of the immune system, but also a cause of several diseases and conditions, including some cancers, rheumatoid arthritis, diabetes, and aging. NLRP3 inflammasome may be an attractive therapeutic target because it is rapidly activated by various inflammatory stimuli or stress signals [4]. Here, we propose ALK as a druggable target in the regulation of uncontrolled NLRP3 inflammasome activation (Fig. 4F). ALK is well-documented to form various fusion genes such as ALK/EML4, ALK/RANBP2, ALK/ATIC, and ALK/NPM1 to drive tumor initiation and development [10]. Beside its function as a fusion protein in cancer cells, wild-type ALK is essential for the development of the nervous system [25], control of ethanol consumption [26,27], and activation of immune cells [12]. Our findings are broadly consistent with those from a recent report showing that ALK is a therapeutic target for lethal inflammation and septic shock [12], but suggest a specific role for ALK-mediated NLRP3 inflammasome activation in macrophages. We observed that ALK inhibitors such as ceritinib and lorlatinib significantly inhibited NLRP3 inflammasome activation. In addition to ALK, other targets have been recognized by ceritinib and lorlatinib, which depends on drug concentration and cell type [28]. Our further RNAi-based approach showed that gene-silencing of ALK blocked NLRP3 inflammasome activation, which confirms that ALK plays a specific role in promoting NLRP3 inflammasome activation in macrophages.