Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome

doi:10.21203/rs.3.rs-3488940/v1

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Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome

https://doi.org/10.21203/rs.3.rs-3488940/v1

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published 13 May, 2024

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The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated tRNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5'-tsRNAs specifically inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5'-tsRNAs recruits DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. In addition, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, which resulted in the amplification of NLRP3 inflammasome-mediated inflammation. This was proved in condition of lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Overall, our study sheds new light on the role of Ang-induced 5'-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.

Biological sciences/Immunology/Cell death and immune response

Biological sciences/Immunology/Inflammation/Inflammasome

inflammation

tsRNAs

NLRP3

angiogenin

stress granule

Excessive activation of the inflammasome is involved in the development of several inflammatory disorders, including atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, sepsis, and type-2 diabetes (T2D)[1, 2]. The inflammasome is a cytosolic multimeric protein complex composed of the nucleotide-binding domain and leucine-rich repeat containing proteins (NLRs) or AIM2, adaptor protein ASC and Caspase-1. The NLRP3 inflammasome can be triggered by a variety of stimuli, including infection, tissue damage, and metabolic dysregulation, and then activated through an integrated cellular stress signal. Activation of NLRP3 inflammasome triggers the caspase-1-dependent maturation and release of several pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18[3-5]. Caspase-1 can also cleave gasdermin D (GSDMD) to generate GSDMD-NT, which forms plasma membrane pores to induce pyroptosis and release pro-inflammatory cytokines[6]. Thus, a better understanding of cellular stress that occurs with the activation of NLRP3 inflammasome may provide a new therapeutic or pharmacological option for the treatment of inflammatory disease.

The tRNA-derived small RNAs (tsRNAs; also known as tRNA-derived fragments, tRFs) are a group of novel small non-coding RNAs that are cleaved from the anticodon loop of mature tRNAs in response to cellular stressors such as infection, tissue damage, and metabolic dysregulation[7-9]. Recent evidence has shown that tsRNAs are involved in multiple biological processes, such as regulating translation[10, 11], apoptosis[12], and intergenerational phenotype transmission[13-15]. The RNase A family member angiogenin (Ang) mediates the cleavage of mature tRNAs within the anticodon loops, producing 30-35 nt 5’-tsRNAs (also known as 5’-tRNA halves or tRNA-derived stress-induced RNAs, tiRNAs) and 40-50 nt 3’-tsRNAs[10, 16-19]. During stress, the activation of Ang facilitates tRNA fragmentation, leading to excessive amounts of tsRNAs and possibly eliciting pathophysiological conditions[15, 20]. Increasing evidence indicates that tsRNAs are exceedingly more expressed in the immune system, such as hematopoietic and lymphoid tissues than other tissues[21, 22]. Furthermore, Ang-induced tsRNAs have significant regulatory roles in various pathological conditions, particularly those related to inflammatory diseases[21-27]. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications for regulating inflammatory diseases remains poorly understood.

Researchers have proposed that Ang-induced tsRNAs may contribute to the formation of stress granules (SGs) as a response to cellular stress. These are non-membrane-bound cytoplasmic structures that contain RNA and RNA-binding proteins (RNPs)[28-30]. Recently, Drino et al. reported that tsRNAs bind to the RNA helicase DEAD-box helicase 3 X-linked (DDX3X) and facilitate the formation of SGs[31]. Interestingly, DDX3X competitively binds to the NACHT domain of NLRP3, thereby inhibiting inflammasome activation[32-34]. Therefore, DDX3X sits at a crossroads between inflammation and stress adaptation and acts as a live-or-die checkpoint in the stressed cells[32, 35, 36]. Thus, it is of interest to investigate whether tsRNAs regulate inflammasome activation via SGs assembly.

One particular stressor that is known to cause robust tRNA cleavage into tsRNAs via Ang and the subsequent formation of SGs is sodium arsenite (hereafter referred to as Ar)[18, 29, 37, 38]. However, there are contradictory results with regard to the effects of Ar on the activation of NLRP3 inflammasome[32, 39-42]. Some studies proposed that Ar can trigger pyroptosis by activating the NLRP3 inflammasome[40-42], whereas others suggested that Ar may decrease NLRP3 inflammasome activation[32, 43]. Therefore, we used Ar to induce the accumulation of tsRNAs in bone marrow-derived macrophages (BMDMs). This served as the model to investigate the potential crosstalk between tsRNAs and the NLRP3 inflammasome. We also explored the potential involvement of Ang-induced tsRNAs in the regulation of systemic inflammation induced by lipopolysaccharide (LPS) and inflammation related to type 2 diabetes (T2D). Our work demonstrates that Ang-induced tsRNAs are endogenous regulators of NLRP3 inflammasome activation and might be a promising target for the treatment of NLRP3 inflammasome-related inflammatory diseases.

Ar induces activation of NLRP3 inflammasome and accumulation of tsRNAs

There are contradictory results concerning the activation of the NLRP3 inflammasome by Ar[32, 40-43]. To assess the effect of Ar on the activation of NLRP3 inflammasome, BMDMs were stimulated with varying concentrations. The findings demonstrate that treatment of Ar promotes the cleavage of Caspase-1 and GSDMD (Figure 1A). Additionally, Ar treatment resulted in increased secretion of leaderless pro-inflammatory cytokines such as IL-1β and TNFα (Figure 1B-C). NLRP3-dependent, ASC nucleation-induced oligomerization is considered to be a common mechanism of NLRP3 inflammasome activation[44]. We found that Ar-induced activation of NLRP3 inflammasome resulted in the condensation of ASC, which formed a large cytosolic speck within each cell (Figure 1D-E). We subsequently verified these phenomena in vivo by intraperitoneally injecting Ar into wild-type mice for 6 and 24 h. Following the treatment, there was a significant increase in the protein levels of caspase1-p20 (cleaved caspase1) in the liver (Figure 1F-G). Taken together, these results indicated that Ar induces activation of NLRP3 inflammasome in vivo and in vitro.

To confirm the effect of Ar on tRNA cleavage, we conducted an analysis of Ang and tsRNAs expression in both liver tissue and BMDMs, where Ang is known to be highly expressed. As expected, the expression level of Ang was upregulated in liver tissue after Ar treatment (Figure 1F, H). It has been reported that tRNA-Gly and tRNA-Glu are more responsive to Ang[15, 45]. Here, we found that the levels of 5’-tsRNA-Gly and 5’-tsRNA-Glu were upregulated by Ar treatment in liver (Figure 1I). Moreover, the expression levels of Ang (Figure 1J-K), and 5’-tsRNA-Gly (Figure 1L), were upregulated in BMDMs after Ar treatment. Overall, these findings show that Ar induces the accumulation of tsRNAs in vivo and in vitro.

Ang mediated 5’tsRNAs alleviate Ar-induced activation of NLRP3 inflammasome

It was known that Ang-induced tsRNAs deficiency exacerbates the development of inflammatory diseases[25, 46, 47]. The BMDMs form Ang^+/+ and Ang^-/- mice were primed by LPS and then treated with Ar. Ar-treated Ang^-/- BMDMs showed more activation of NLRP3 inflammasome than Ang^+/+BMDMs, as evidenced by the increase of cleaved Caspase1 and GSDMD (Figure 2A). Moreover, the secretion of IL-1β was significantly higher in Ar-treated Ang^-/- BMDMs compared with Ang^+/+ BMDMs (Figure 2B). In contrast, no significant difference in TNFα secretion which were Caspase-1-independent (Figure 2C). In addition, the percentage of cells that contained ASC specks was significantly increased in Ar-treated Ang^-/- BMDMs compared with Ang^+/+ BMDMs (Figure 2D-E). All results indicating that Ang deficiency exacerbate sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis.

To investigate whether Ang mediated 5’tsRNAs could mitigated the activation of NLRP3 inflammasome, a mixture of the 5'-tsRNAs expressed most abundantly was synthesized, and then transfected into BMDMs using established protocols (Supplementary Table 1; Supplementary Figure 1)[28, 48]. Pretreatment with tsRNAs alleviated Ar-induced activation of NLRP3 inflammasome, as indicated by the downregulation of cleaved Caspase1 and GSDMD (Figure 2F). Moreover, the secretion of IL-1β was decreased by tsRNAs transfection (Figure 2G). In contrast, Ar-induce TNFα secretion was not affected by the addition of tsRNAs (Figure 2H). Furthermore, tsRNAs pre-treatment significantly decreased the percentage of cells that contained ASC specks compared with cells that were treated with Ar alone (Figure 2I-J). Overall, these findings suggest that tsRNAs mitigated the activation of NLRP3 inflammasome induced by Ar.

It has been reported that Ang-induced tsRNAs inhibit global translation in several cell types[9, 10]. To investigate whether tsRNAs-induced inhibition of NLRP3 inflammasome activation by an arrest of translation, we checked the protein levels of NLRP3, pro-IL-1β (the inactive cytoplasmic precursor of IL-1β), and pro-caspase1 (the inactive cytoplasmic precursor of caspase1). The results showed that the levels of NLRP3, pro-IL-1β, and pro-caspase1 were unaffected by tsRNAs transfection (Supplementary Figure 2). This suggests that tsRNAs-induced inhibition of NLRP3 inflammasome activation is independent of translation.

tsRNAs recruit DDX3X into SGs to alleviate the activation of NLRP3 inflammasome

It has been reported that Ang-induced tsRNAs can promote the assembly of stress-induced SGs[28, 29]. However, a recent study reported that neither physiological nor non-physiological concentrations of tsRNAs were able to induce the formation of SGs[49]. To investigate the involvement of tsRNAs in the formation of SGs, we transfected a pool of synthesized 5'-tsRNAs into BMDMs and then induced SGs formation by Ar. Specifically, confocal microscopy imaging of G3BP1, a marker of SGs, revealed that Ar treatment induced the formation of SGs in LPS-primed BMDMs (Figure 3A). Transfection of 5'-tsRNAs into BMDMs did not affect the percentage of cells that contained SGs, compared with cells that were treated with Ar alone (Figure 3A-B). However, the percentage of cells containing 6-10 SGs were increased (Figure 3A, C). To further confirm whether SGs mediated tsRNAs-induced inhibition of NLRP3 inflammasome activation, we treated BMDMs with anisomycin (An, the inhibitor of SGs[32]) to inhibited Ar-induced SGs assembly (Figure 3A, D). This treatment reduced SGs assembly and blocked tsRNAs-induced inhibition of NLRP3 inflammasome activation (Figure 3E), with the secretion of IL-1β but not TNFα in supernatants significantly increasing upon treatment with An (Figure 3F-G). Moreover, co-treatment with An showed a significant increase in the percentage of cells containing ASC specks (Figure 3H-I). To further confirm the involvement of SGs in tsRNAs-triggered suppression of NLRP3 inflammasome activation, we employed another system of pyroptosis and NLRP3 inflammasome activation by LPS priming followed by nigericin (Nig) treatment. Consistent with existing findings, we observed no SGs assembly in BMDMs subjected to LPS priming followed by Nig treatment (Supplementary Figure 3E)[32].Subsequently, we transfected BMDMs with 5’-tsRNAs and then exposed them to LPS priming followed by Nig treatment. We observed no significant difference in the cleavage of Caspase-1 and GSDMD, secretion of IL-1β and TNFα, or ASC speck formation in BMDMs with or without tsRNAs (Supplementary Figure 3A-D). Taken together, these findings suggest that SGs assembly is essential for tsRNAs-mediated inhibition of NLRP3 inflammasome activation.

Next, we investigated the mechanism underlying how tsRNAs alleviate the activation of NLRP3 inflammasome. It had been suggested that DDX3X, an ATP-dependent RNA helicase present in SGs, interacts with NLRP3 and facilitates the activation of inflammasomes^[32]. However, the formation of SGs causes DDX3X to be sequestered, thereby inhibiting NLRP3 inflammasome activation[32]. Recent findings indicated that there is a direct association among DDX3X, tRNAs, and tsRNAs[31]. Moreover, Ang-induced tsRNAs can be incorporated into SGs[29]. Therefore, we hypothesized that Ang-induced tsRNAs have the ability to contend with DDX3X molecules, thereby diminishing the activation of both NLRP3 inflammasome and SGs. Confocal microscopy imaging demonstrated that the transfection of tsRNAs led to the co-localization of DDX3X and G3BP1 (Figure 4A). Conversely, transfection of tsRNAs resulted in a decrease of NLRP3 co-localization with DDX3X (Figure 4B). Additionally, Co-immunoprecipitation (Co-IP) also confirmed that there was an interaction between DDX3X and NLRP3 (Supplementary Figure 4). Moreover, tsRNAs treatment reduced the binding between DDX3X and NLRP3 (Figure 4C). No significant difference in cells with stress granules between Ar-treated Ang^+/+ BMDMs and Ang^-/- BMDMs (Figure 4D). Confocal microscopy imaging showed that Ar-treated Ang^-/- BMDMs resulted in a decrease of G3BP1 co-localization with DDX3X (Figure 4E). Conversely, the co-localization of NLRP3 and DDX3X was increased in Ar-treated Ang^-/- BMDMs (Figure 4F). These findings provide evidence of physical interaction between NLRP3 and DDX3X, supporting the notion that tsRNAs augment the recruitment of DDX3X into SGs and decrease the interaction between DDX3X and NLRP3, thereby mitigating the activation of NLRP3 inflammasome.

Ang deficiency aggravates LPS-induced systemic inflammation

We subsequently explored whether Ang-induced tsRNAs were involved in the regulation of inflammatory responses via inhibiting the activation of NLRP3 inflammasome in vivo. We first investigated the effect of LPS on the hepatic expression of Ang and the production of tsRNAs in mice. Our results showed a noteworthy increase in the expression of Ang after LPS treatment (Figure 5A-C). Moreover, Ang-induced tsRNAs (5’-tsRNA-Gly and 5’-tsRNA-Glu) were upregulated in LPS-treated mice, whereas their expression levels were reversed upon Ang deletion (Figure 5D). To further confirm the impact of Ang on the activation of NLRP3 inflammasome during LPS-induced systemic inflammation, we measured the concentration of IL-1β and IL-18 in serum. Our findings showed that both of them were significantly higher in LPS-treated Ang^-/- mice compared with Ang^+/+ mice (Figure 5E-F). Conversely, Ang deficiency had a limited effect on serum TNFα production (Figure 5G). These results suggest that the absence of Ang-induced tsRNAs exacerbates the development of inflammasome-dependent inflammatory diseases.

Ang deficiency aggravates high-fat diet-induced insulin resistance

Increasing evidence suggests that chronic NLRP3-mediated inflammation plays a role in the development of insulin resistance and T2D[50-52]. To determine whether Ang-induced tsRNAs play a role in regulating obesity-related insulin sensitivity by inhibiting NLRP3 inflammasome activation, we subjected Ang^+/+ and Ang^-/- mice to a high-fat diet (HFD) or a normal diet (ND) for a period of 14 weeks. Firstly, we observed that the expression of Ang was upregulated in the liver of HFD mice (Figure 6A-C). Moreover, Ang-induced tsRNAs (5’-tsRNA-Gly and 5’-tsRNA-Glu) were upregulated in the liver of HFD mice, whereas their expression levels were reversed upon Ang deletion (Figure 6D). Subsequently, we aimed to investigate if Ang-induced tsRNAs could enhance obesity-related insulin sensitivity. As anticipated, Ang^+/+ mice exhibited glucose intolerance and insulin resistance after being subjected to the HFD treatment (Figure 6E-H). However, the Ang^-/--HFD mice showed significantly higher glucose than other mice, as revealed by glucose tolerance test (GTT) and insulin tolerance test (ITT) assays. These results suggest that Ang-induced tsRNAs are implicated in the development of glucose intolerance and insulin resistance induced by HFD (Figure 6E-H). Furthermore, to investigate the impact of Ang deficiency on the inflammatory response induced by metabolic stress, tissue culture assays were performed ex vivo. Results were consistent with those obtained above, with liver tissue (Figure 6I-J) and wite adipose tissue (WAT) (Figure 6K-L) from Ang^+/+-HFD mice showing higher IL-1β and TNFα production compared with Ang^+/+-ND mice. In contrast, IL-1β levels in the liver and WAT (Figure 6I, K) were higher in Ang^-/--HFD mice than in Ang^+/+-HFD mice, whereas, TNFα demonstrated no significant differences between the two groups (Figure 6J, L). Taken together, these findings suggest that Ang-induced tsRNAs contribute to HFD-induced glucose intolerance and insulin resistance through activation of the NLRP3 inflammasome via metabolic stress.

In recent years, increasing evidence has shown that both Ang and tsRNAs play essential roles in the development of various inflammatory diseases. We show here that Ang-induced tsRNAs specifically targets the NLRP3 inflammasome, achieving effective suppression of inflammation and promoting potent anti-inflammatory effects in inflammatory disorders. Mechanistically, we found that tsRNAs recruit the DDX3X protein into SGs, thereby preventing the interaction between DDX3X and NLRP3, which activates the NLRP3 inflammasome (Fig. 7). Additionally, in vivo experiments showed that Ang deficiency resulted in the downregulation of 5'-tsRNAs, leading to the amplification of NLRP3 inflammasome-dependent inflammation, including LPS-induced systemic inflammation and T2D-related inflammatory responses.

It is well-established that competition for DDX3X molecules between SGs and the NLRP3 inflammasome is essential in coordinating the activation of innate responses and subsequent cell fate decisions during stress conditions[32, 35, 36]. However, the mechanism underlying the incorporation of DDX3X into SGs remains unclear. Upon stress, the activation of Ang promotes tRNA fragmentation, leading to excessive production of tsRNAs and potentially regulating pathophysiological conditions[15, 20]. Ang-induced tsRNAs have the ability to trigger the formation of SGs, and can subsequently be incorporated into these structures[29]. It has been observed that Ang-induced tsRNAs can form an RNP complex with cytochrome c, which is released from the mitochondria, and that the tsRNA-mediated sequestration of cytochrome c fosters cell survival by preventing apoptosome formation and apoptosis under cellular stress[12]. In the present study, we found that the transfection of 5’-tsRNAs into BMDMs did not affect the percentage of cells with or without SGs. It is consistent with a recent report, which suggested that neither physiological nor non-physiological levels of tsRNAs were able to induce the formation of SGs[49]. However, inhibition of Ar-induced SGs assembly reduced tsRNAs-induced inhibition of NLRP3 inflammasome activation. In addition, we observed that 5'-tsRNAs were unable to prevent NLRP3 inflammasome activation by stimulating BMDMs with LPS and Nig due to no assembly of SGs. Together, this suggests that SGs assembly is essential for tsRNAs-mediated inhibition of NLRP3 activation. Recently, Drino et al. reported that the RNA helicase DDX3X binds to tsRNAs and assists in the formation of SGs[31]. Here, we found that tsRNAs treatment reduced the binding between DDX3X and NLRP3 but promoted the co-localization of DDX3X and G3BP1. This suggests a strong possibility for interaction between tsRNAs and DDX3X during the activation of the NLRP3 inflammasome. Our collective findings indicate that tsRNAs are involved in the recruitment of DDX3X into SGs, and the absence of DDX3X hinders the activation of the NLRP3 inflammasome.

Recently, both human clinical studies and animal experiments have demonstrated that Ang and tsRNAs have anti-inflammatory activity and beneficial roles in a variety of human inflammatory diseases, including inflammatory bowel disease, Parkinson’s disease, and cancers[25, 46, 47]. It is worth noting that the levels of tsRNAs were observed to be dramatically elevated following SARS-CoV-2 infection, particularly in coronavirus disease 2019 (COVID-19) patients with severe symptoms[53]. Additionally, the levels of tsRNAs were upregulated in serum samples from patients with chronic hepatitis B virus infection[8]. Thus, an understanding of the underlying anti-inflammatory mechanisms provides for the appropriate use of Ang and tsRNAs in the clinic. We and other researchers have discovered that LPS can lead to a rapid increase in levels of tsRNAs in various tissues and body fluids, including serum, spleen, intestine, epididymis, and sperm in mouse and monkey models[8, 15, 54]. Here, we show that Ang deficiency resulted in the downregulation of tsRNAs, thereby upregulating NLRP3 inflammasome-dependent inflammation (increasing serum levels of IL-1β and IL18). Conversely, Ang deficiency had little effect on TNFα production in the serum. Our results highlight that the absence of Ang-induced tsRNAs exacerbates the development of inflammasome-dependent inflammatory diseases.

T2D is a leading cause of morbidity and mortality worldwide and its etiology remains unclear. Several cellular stress response mechanisms have been proposed to elucidate the insulin resistance and islet β-cell dysfunction in T2D, including oxidative stress and endoplasmic reticulum stress[55, 56]. It is noteworthy that each of these cellular stresses is also believed to trigger or be associated with an inflammatory response. Indeed, increasing evidence suggests chronic inflammation as an important pathogenetic factor in the development of insulin resistance and T2D[57, 58]. Numerous SGs have been found in macrophages and fatty liver tissues of HFD-fed obese mice[59]. However, the role of SGs in the pathogenesis of obesity and related diseases remains unclear. Moreover, levels of tsRNAs were upregulated in the sperm of HFD mice[13, 60]. In the present study, HFD induced upregulation of Ang and Ang-mediated tsRNAs in the liver of Ang^+/+-HFD but not Ang^−/−-HFD mice. In addition, liver tissue culture assays indicated that Ang deficiency boosts metabolic stress and NLRP3 inflammasome activation. We suppose that tsRNAs recruit DDX3X into SGs which block the interaction between DDX3X and NLRP3, alleviating the activation of NLRP3 inflammasome. As a result, the Ang^−/−-HFD mice showed lower glucose intolerance and insulin resistance. Collectively, these results indicate that Ang-induced tsRNAs are involved in HFD-induced glucose intolerance and insulin resistance via NLRP3 inflammasome during metabolic stress.

In summary, our study identifies the role of Ang-induced tsRNAs in the regulation of NLRP3 inflammation activation in vitro and in vivo. It is revealed that (i) Ang-induced tsRNAs alleviate the activation of NLRP3 inflammasome; (ii) tsRNAs recruit DDX3X into SGs which block the interaction between DDX3X and NLRP3; (iii) Ang deficiency results in the downregulation of tsRNAs, which in turn amplifies NLRP3 inflammasome-mediated inflammation and metabolic disorder. In light of our findings, targeting Ang-induced tsRNAs might lead to insights and treatments for NLRP3 inflammasome-related diseases.

Generation of transgenic mouse models and mouse breeding

Wild-type C57BL/6 mice and Ang^-/- mice (Strain NO. T011609) were purchased from GemPharmatech (Nanjing, China). Ang^-/- mice used CRISPR/Cas9 technology to edit the Ang gene. The Ang gene has 2 transcripts. According to the structure of Ang gene, exon2 of Ang-202 (ENSMUST00000171688.8) transcript is recommended as the knockout region. The region contains all of the coding sequence. Knock out the region will result in disruption of protein function. The brief process is as follows: sgRNA was transcribed in vitro. Cas9 and sgRNA were microinjected into the fertilized eggs of C57BL/6JGpt mice. Fertilized eggs were transplanted to obtain positive F0 mice which were confirmed by PCR and sequencing. A stable F1 generation mouse model was obtained by mating positive F0 generation mice with C57BL/6JGpt mice. All mice were fed in specific pathogen-free conditions at the Laboratory Animal Center of Nanjing Agricultural University. They accessed food and water ad libitum and were housed in a 12 h light/12 h dark artificial lighting cycle room, the room temperature is 22-25°C with 40%-60% humidity. Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Agricultural University. All experiments followed the “Guidelines on Ethical Treatment of Experimental Animals” (2006) No. 398 set by the Ministry of Science and Technology, China, and Regulation regarding the Management and Treatment of Experimental Animals” (2008) No. 45 set by the Jiangsu Provincial People’s Government.

For Ar induced inflammatory model, 8-week-old male mice were injected intraperitoneally with Ar (4 mg/kg BW). Mice were killed after 0, 6, and 24 h, and the liver was collected for future analysis. For LPS-induced sepsis, 8-week-old male Ang^+/+and Ang^-/- mice were injected intraperitoneally with LPS (20 mg/kg BW), which was derived from E. coli (strain O111:B4) (L2880, Sigma), whereas, control mice were injected with the same volume (100 μL) of saline. Mice were killed after 4 h, and serum was measured by ELISA. For metabolic stress studies, 4-week-old Ang^+/+and Ang^-/- mice were maintained on ND, HFD (60% cal/fat, D12492; Research Diets) for 14 weeks.

Cell culture and stimulation

BMDMs were collected and cultured as described[61]. Six weeks-old mice were euthanatized via cervical dislocation. Femurs and tibias were collected in cold PBS. Both ends of the bone were cut and the bone marrow was flushed out into 50 mL centrifugal tube with cold PBS. The cells were then gently blown into a single-cell suspension and passed through a 70 μm sterile strainer. Following centrifuge at 1400 rpm for 5 min, the supernatant was decanted and red blood cells were lysed using Red Blood Cell lysis buffer (C3702, Beyotime) for 5 min. After neutralization with DMEM (319-005-CL, Vicente Biotechnology), bone marrow cells were centrifuged at 1400 rpm for 5 min. After washing twice with cold PBS, cells were resuspended in DMEM containing 20 ng/mL M-CSF (315-02, PeproTech), 10% FBS (10100147c, Gibco), 1% penicillin (100 U/mL) and streptomycin (100 μg/mL) (PS, C0222, Beyotime) and placed into 6 well plates (2×10⁶ cells/mL). After 3 days of culture, the medium was completely replaced, and after 2 days, half of the medium was changed. The differentiated BMDMs were then treated with further stimulation on the sixth day. All steps were performed under sterile conditions.

For tsRNAs transfection, BMDMs were transfected with 200 nM total tsRNAs (Supplementary Table 1) by Lipofectamine RNAiMAX transfection reagent (13778150, Invitrogen). After 2 h, BMDMs were primed with 500 ng/mL LPS for 4 h, then treated with 50 μM Ar (Sigma-S7400) for 1 h to induce SGs formation. To inhibit SGs formation, 2 μg/mL An (GC11559-10, Glpbio) was added into the LPS-primed BMDMs 20 min before Ar.

Western blot

Tissue samples (30 mg) were homogenized using 1 mL lysis buffer (P0013B, Beyotime), which contains 1× protease inhibitor (K1007, APExBIO) and 1× Phosphatase inhibitor (K1015, APExBIO). After centrifuging at 4℃, 12000 g for 10 min, the supernatant was collected. For cells, we added 50 μL lysis buffer for BMDMs per 6-well plate. The protein content was determined using the BCA protein assay kit (P0012S, Beyotime) according to the manufacturer’s protocol. Protein samples were separated using 6%-12% SDS polyacrylamide gels and transferred onto polyvinylidene fluoride membrane (IPVH00010, Millipore) at 100 V for 1.5 h. Then the membranes were incubated with 5% milk for 2 h at room temperature. After that, membranes were incubated with the primary antibodies at 4℃, with gentle shaking overnight. The primary antibodies used were rabbit anti-NLRP3 (1:1000, #15101, Cell Signaling Technology), mouse anti-Caspase1 (1:1000, AG-20B-0042, AdipoGen), rabbit anti-GSDMD (1:1000, ab219800, Abcam), rabbit anti-IL-1β (1:1000, ab254360, Abcam) and anti-Tubulinα (1:1000, AC007, ABClonal). Images were captured using the VersaDoc 4000MP system (Bio-Rad, Hercules, CA) and the band density was analyzed with ImageJ.

ELISA

Supernatants from cell culture or tissue culture as well as serum were assayed for mouse IL-1β (EK201B, MULTI SCIENCE), IL-18 (ELM-IL18, RayBiotech), and TNFα (CSB-E04741m, CUSA BIO) according to manufacturer’s instructions.

Immunofluorescence

BMDMs were fixed in 4% paraformaldehyde for 10 min at room temperature, then incubated with 0.3% Triton X-100 membrane permeabilization solution (TBST) for 1 h at room temperature. After 10 min in blocking buffer (5% bovine serum albumin in TBST) at RT, BMDMs were subsequently incubated with primary antibody overnight at 4°C. The antibody reagents were rabbit anti-ASC antibody (1:800, #67824, Cell Signaling Technology), rabbit anti-G3BP1 antibody (1:600, 13057-2-AP, Proteintech), rabbit anti-NLRP3 antibody (1:200, 15101, Cell Signaling Technology) or mouse anti-DDX3X antibody (1:100, sc-365768, Santa Cruz) overnight at 4°C. The next day, incubation was done at 37℃ for 30 min, then washed 3 times with TBST, and latter incubated with Alexa Fluor 488 (1:200, SA00013-3, proteintech) secondary antibody for 1 h at 37°C. Washing was repeated thrice with TBST and then incubated with DAPI (C1005, Beyotime) for 5 min.

Northern blot

Total RNA was extracted from mouse tissues or BMDMs using TRIzol reagents (TSP401, Tsingke). RNA was separated by 15% urea-PAGE gel, stained with TS-GelRed (1:10000, TSJ002, TSINGKE), and immediately imaged and transferred to nylon membranes (FFN13, Beyotime), then crosslinked for 2 h at 80°C. Membranes were pre-hybridized with ULTRAhyb® Ultrasensitive Hybridization Buffer (AM8670, Invitrogen) for at least 1 h at 42°C. The membranes were incubated with 16 nM DIG-labeled oligonucleotides probes overnight (12–16 h) at 42°C. The probes were synthesized by GENEWIZ, Inc. as shown in Supplementary Table 2. The membranes were washed twice with a low stringent buffer (2× SSC with 0.1% (wt/vol) SDS) at 42°C for 15 min each time, then washed twice with a high stringent buffer (0.1× SSC with 0.1% (wt/vol) SDS) for 5 min each time, finally rinsed in washing buffer (1× SSC) for 10 min. Following the washes, the membranes were transferred into 1× blocking buffer (REF:11096176001, Roche) and incubated at room temperature for 2 h, after that, the DIG antibody, Anti-Digoxigenin-AP Fab fragments (REF: 11093274910, Roach) was added into the blocking buffer at a ratio of 1:10,000 and incubated for half an hour at room temperature. The membranes were then washed four times in DIG washing buffer (1× maleic acid buffer, 0.3% Tween-20) for 15 min each time, rinsed in DIG detection buffer (0.1 M Tris-HCl, 0.1 M NaCl, pH 9.5) for 5 min, and then incubated with CSPD ready-to-use reagent (REF: 11755633001, Roach). The membranes were incubated with the CSPD reagent at 37°C for 15 min in the dark. Images were capturedusing the VersaDoc 4000MP system (Bio-Rad, Hercules, CA).

Co-immunoprecipitation (Co-IP)

Whole-cell extracts were lysed in IP buffer (Beyotime, P0013, Shanghai, China), which contained 1× protease inhibitor (K1007, APExBIO) and 1× Phosphatase inhibitor (K1015, APExBIO). The protein concentration was detected and diluted to a final concentration of 000 ng/μL after ultrasonication. Firstly, the supernatants were incubated with protein G Plus-Agarose Immunoprecipitation reagent (sc-2003, Santa Cruz) for 2 h to remove unless specifically bound proteins. The Plus-Agarose Immunoprecipitation reagent was removed and incubated with NLRP3 antibodies (1:200) overnight at 4℃. The next day, protein G Plus-Agarose Immunoprecipitation reagent was added to the supernatants overnight at 4℃. Afterwards, all beads were washed three times with PBS which contained 1× protease inhibitor and 1× Phosphatase inhibitor. Then 2× loading buffer was added to each sample and boiled at 100°C for 5 min followed by western blotting.

Blood glucose examination during GTT and ITT

For GTT, mice were injected intraperitoneally with glucose (2 g/kg body weight) after 12 h fasting. For ITT, mice were intraperitoneally injected with insulin (0.75 IU/kg, 12584-586, Aladdin) after 6 h fasting. Blood samples were collected from the tail vein before glucose or insulin injection (0 min) and at 15, 30, 60, and 120 min afterward. Blood glucose was immediately determined by Accu-Chek glucose meters (ACCUCHEK Active Blood Glucose Meter, Roche) at different time points.

Tissue culture

The isolated liver and WAT tissues were washed twice in PBS, minced into fine pieces, and cultured in 12-well plates (0.5 g/well) in M199 medium (P012, Nanjing Jiancheng Bioengineering Institute) supplemented with 5% FBS, penicillin and streptomycin. After 24 h, culture supernatants were analyzed by ELISA kit for IL-1β and TNFα.

qRT-PCR

Total RNA was extracted the same as before^[15]. The mRNA level of Ang was assessed using qRT-PCR. The primers for amplifying mouse Ang were purchased from Beijing Tsingke Biotech Co., Ltd.: forward, 5′-AGCGAATGGAAGCCCTTACA-3′; reverse, 5′- CTCATCGAAGTGGACAGGCA-3′.

Statistical analysis

All analyses were performed with GraphPad Prism 8 (GraphPad Software). Data were presented as mean with standard error of the mean (SEM) or violin plot. The difference between two groups was assessed using unpaired two‐tailed Student's t‐test or Mann–Whitney test for non‐normally distributed data. The difference between variables was assessed by one‐way ANOVA with Dunnett's multiple comparisons test or Kruskal–Wallis with Dunn's multiple comparisons test for nan‐normally distributed data. Equality of survivor function was determined by log‐rank test. A P‐value < 0.05 was considered statistically significant; P‐value results were denoted by asterisks in the figures (*P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001). The detailed statistical analysis and replicate numbers for each experiment were described in the figure legends, and the exact P‐value can be found in the corresponding source data file.

DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

AUTHOR CONTRIBUTIONS

J.C. contributed to conceptualization, investigation, formal analysis, validation, visualization, writing-original draft, review, and editing. C.L. contributed to investigation, formal analysis and methodology. S.L. contributed to investigation and formal analysis. M.T. contributed to investigation and validation. X.S. contributed to investigation and validation. M.Y. contributed to investigation and validation. B.H. contributed to conceptualization, resources, writing-review and editing, supervision, project administration, and funding acquisition.

FUNDING

This work was supported by the National Key Research and Development Program of China (2022YFD1300405), the National Natural Science Foundation of China (32372965, 32072807), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

COMPETING INTERESTS

The authors declare no competing interests.

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Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome

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