Proline/serine-rich coiled-coil protein 1 alleviates pyroptosis in murine bone marrow-derived macrophages

Abstract

Pyroptosis is a regulated inflammatory cell death process that plays an essential role in various diseases. This study investigates the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in pyroptosis and inflammation in macrophages. This study reports that PSRC1 expression is decreased in pyroptotic macrophages and that knockout of PSRC1 exacerbates pyroptosis and inflammation. PSRC1 overexpression alleviates pyroptosis and inflammation in macrophages. RNA-seq analysis reveals that PSRC1 regulates the expression of genes involved in the extracellular matrix (ECM). Specifically, PSRC1 downregulates the expression of periostin (POSTN), an ECM component. Knockdown of POSTN suppresses macrophage pyroptosis mediated by low expression of PSRC1. These findings suggest that PSRC1 can alleviate pyroptosis and inflammation in bone marrow-derived macrophages (BMDMs) by regulating the ECM and negatively regulating POSTN. This study provides insights into the role of PSRC1 in macrophage pyroptosis and identifies a potential target for the treatment of inflammatory diseases. Further research is needed to confirm these findings in vivo and in various disease models.

1. Introduction

Pyroptosis is a form of regulated inflammatory cell death that involves the cleavage of gasdermin proteins [1]. Upon stimulation of macrophages with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), inflammasomes such as NLRP3 and ASC are activated [2]. The activated inflammasome binds to Caspase-1 or Caspase-11 (or human Caspase-4/-5) and facilitates its activation through cleavage. Cleaved caspases trigger the cleavage of gasdermin-D (GSDMD) into GSDMD-C and GSDMD-N, with GSDMD-N subsequently forming membrane pores [1]. Caspases also promote the maturation and cleavage of IL-1β and IL-18, which are released through GSDMD-N pores. This process leads to cell swelling and the release of additional intracellular proinflammatory cytokines [3]. Pyroptosis is also known to play a significant role in the pathology of numerous diseases, such as atherosclerosis, Alzheimer′s disease, inflammatory bowel disease and various infectious diseases [4–7]. The identification of molecules involved in pyroptosis is crucial for understanding its mechanisms.

Proline/serine-rich coiled-coil protein 1 (PSRC1), also known as DDA3, belongs to the microtubule-associated protein (MAP) family [8,9]. MAPs play various roles within cells, including signal transduction, metabolic regulation, and material transport [10–12]. Genome-wide association studies (GWASs) have also highlighted the strong association between PSRC1 and coronary artery disease (CAD) [13]. Additionally, our previous study revealed that PSRC1 decreased the phosphorylation of NF-κB and inhibited the release of IL-1β, IL-6, and TNF-α in macrophages [14]. Another study revealed that PSRC1 alleviates atherosclerosis and inhibits inflammation by binding to Annexin A2 (ANXA2) in macrophages [15]. Pyroptosis is a form of regulated inflammatory cell death, but whether PSRC1 alleviates macrophage inflammation via pyroptosis remains unexplored. Taken together, the impact and mechanism of PSRC1 on macrophage pyroptosis have yet to be determined.

Periostin (POSTN) is a matricellular protein of the ECM [16]. The ECM acts as a PAMP or DAMP, stimulating pyroptosis [17]. Several studies have indicated the involvement of POSTN in inflammatory responses. POSTN also aggravated Caspase-1-mediated pyroptosis [18]. In this study, we aimed to investigate the role of PSRC1 in macrophage pyroptosis. We showed that the expression of PSRC1 is downregulated in the process of macrophage pyroptosis. By generating PSRC1-knockout bone marrow-derived macrophages (BMDMs), we further found that PSRC1 mitigates macrophage pyroptosis and the accompanying proinflammatory cytokines. Pyroptosis and inflammatory responses are aggravated in PSRC1-deficient BMDMs. In contrast, overexpression of PSRC1 ameliorates pyroptosis. Through RNA-seq analysis and experimental validation, we further revealed that POSTN mediates this effect and that aggravated pyroptosis can be counteracted by downregulating the expression of POSTN. For the first time, we report that PSRC1 downregulates the expression of POSTN, thereby inhibiting macrophage pyroptosis. This work identifies a novel target for modulating pyroptosis in macrophages and reveals a potential mechanism contributing to the pathogenesis of inflammatory diseases.