Targeting the TRAF3-ULK1-NLRP3 regulatory axis to control alveolar macrophage pyroptosis in acute lung injury

Abstract

Acute lung injury (ALI) is a serious condition characterized by damage to the lungs. Recent research has revealed that activation of the NLRP3 inflammasome in alveolar macrophages, a type of immune cell in the lungs, plays a key role in the development of ALI. This process, known as pyroptosis, contributes significantly to ALI pathogenesis. Researchers have conducted comprehensive bioinformatics analyses and identified 15 key genes associated with alveolar macrophage pyroptosis in ALI. Among these, NLRP3 has emerged as a crucial regulator. This study further reveal that the ULK1 protein diminishes the expression of NLRP3, thereby reducing the immune response of alveolar macrophages and mitigating ALI. Conversely, TRAF3, another protein, is found to inhibit ULK1 through a process called ubiquitination, leading to increased activation of the NLRP3 inflammasome and exacerbation of ALI. This TRAF3-mediated suppression of ULK1 and subsequent activation of NLRP3 are confirmed through various in vitro and in vivo experiments. The presence of abundant M0 and M1 alveolar macrophages in the ALI tissue samples further support these findings. This research highlights the TRAF3-ULK1-NLRP3 regulatory axis as a pivotal pathway in ALI development and suggests that targeting this axis could be an effective therapeutic strategy for ALI treatment.

1. Introduction

The role of alveolar macrophages in pulmonary inflammation is significant because these immune cells serve as the first line of defense in the respiratory tract and play a critical role in regulating the host response during microbial infections [1,2]. Alveolar macrophages not only capture and eliminate invading microorganisms but also regulate the inflammatory response, thus shaping the outcome of respiratory infections [3]. Through the production of cytokines and chemokines, alveolar macrophages recruit other immune cells and ensure the clearance of pathogens while preventing tissue damage and promoting tissue repair [4]. Furthermore, dysregulation of alveolar macrophage function has been implicated in the pathogenesis of various pulmonary diseases, highlighting the importance of studying these immune cells in the context of pulmonary inflammation [5,6]. Pyroptosis is a form of regulated cell death triggered by innate immunity, and the pyroptosis of alveolar macrophages is a well-established hallmark of the pathogenesis of acute lung injury (ALI) [7,8]. Macrophages are activated and polarized in response to ALI, and pyroptosis of alveolar macrophages contributes to pulmonary inflammation. Understanding the biological mediators involved in alveolar macrophage pyroptosis and ALI offers the possibility of future investigations targeting treatment based on these mediators.

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF family that plays a crucial and complex signaling role in the immune system and plays a crucial role in regulating immune and inflammatory responses [9]. Recent literature has confirmed that TRAF3 can form a complex with TRAF2 and cellular inhibitor of apoptosis protein-1 (cIAP1) and mediate the ubiquitination and degradation of Unc-51-like autophagy activating kinase 1 (ULK1), thus promoting lipopolysaccharide plus nigericin (LPS/Ng)-induced inflammasome activity and pyroptosis in mouse primary macrophages and human monocyte THP-1 cells [10]. ULK1 functions as a serine/threonine kinase that plays a vital role in human diseases, including cancer, cardiovascular disease and infections [11]. Upregulation of ULK1 has been demonstrated to contribute to increased LPS-induced autophagy, which plays a protective role against LPS-induced ALI [10]. In addition, increased expression of ULK1 results in the inhibition of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, thereby reducing bone metastasis [12]. NLRP3 is an intracellular receptor that assembles with apoptosis-associated speck-like protein containing a caspase recruitment domain and caspase-1 to form a multimeric protein named the NLRP3 inflammasome, which can trigger the release of proinflammatory cytokines and promote gasdermin D (GSDMD)-mediated pyroptosis [13]. Notably, NLRP3 inflammasome activation facilitates alveolar macrophage pyroptosis in ALI and thereby accelerates the development of ALI [14,15]. These studies suggest that TRAF3 may be involved in ALI by regulating ULK1 and the NLRP3 inflammasome and facilitating the pyroptosis of alveolar macrophages.

In this study, we aimed to explore whether TRAF3 affects the development of ALI and to uncover the possible mechanisms of TRAF3 in ALI. The findings of this study provide valuable insights into the mechanisms underlying ALI pathogenesis, particularly regarding alveolar macrophage pyroptosis.