{"title":"Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome","authors":"Yan Wang, Guang Xu, Jincai Wen, Xiaomei Zhao, Huanying Zhao, Guiji Lv, Yingjie Xu, Ye Xiu, Junjie Li, Simin Chen, Qing Yao, Yuanyuan Chen, Lina Ma, Xiaohe Xiao, Junling Cao, Zhaofang Bai","doi":"10.1111/imm.13771","DOIUrl":"10.1111/imm.13771","url":null,"abstract":"<p>Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-β, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (<i>Trex1</i>) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"295-312"},"PeriodicalIF":6.4,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-03-05DOI: 10.1111/imm.13775
Georg Lindner, Annika Walter, Clara L. Magnus, Katharina Rosenhammer, Bohdan Holoborodko, Victoria Koch, Sarah Hirsch, Luis Grossmann, Suqi Li, David M. Knipe, Neal DeLuca, Beatrice Schuler-Thurner, Stefanie Gross, Barbara Schwertner, Martina Toelge, Anette Rohrhofer, Sabine Stöckl, Richard J. Bauer, Gertrud Knoll, Martin Ehrenschwender, Sebastian Haferkamp, Barbara Schmidt, Philipp Schuster
{"title":"Comparison of the oncolytic activity of a replication-competent and a replication-deficient herpes simplex virus 1","authors":"Georg Lindner, Annika Walter, Clara L. Magnus, Katharina Rosenhammer, Bohdan Holoborodko, Victoria Koch, Sarah Hirsch, Luis Grossmann, Suqi Li, David M. Knipe, Neal DeLuca, Beatrice Schuler-Thurner, Stefanie Gross, Barbara Schwertner, Martina Toelge, Anette Rohrhofer, Sabine Stöckl, Richard J. Bauer, Gertrud Knoll, Martin Ehrenschwender, Sebastian Haferkamp, Barbara Schmidt, Philipp Schuster","doi":"10.1111/imm.13775","DOIUrl":"10.1111/imm.13775","url":null,"abstract":"<p>In 2015, the oncolytic herpes simplex virus 1 (HSV-1) T-VEC (talimogene laherparepvec) was approved for intratumoral injection in non-resectable malignant melanoma. To determine whether viral replication is required for oncolytic activity, we compared replication-deficient HSV-1 <i>d</i>106S with replication-competent T-VEC. High infectious doses of HSV-1 <i>d</i>106S killed melanoma (<i>n</i> = 10), head-and-neck squamous cell carcinoma (<i>n</i> = 11), and chondrosarcoma cell lines (<i>n</i> = 2) significantly faster than T-VEC as measured by MTT metabolic activity, while low doses of T-VEC were more effective over time. HSV-1 <i>d</i>106S and, to a lesser extent T-VEC, triggered caspase-dependent early apoptosis as shown by pan-caspase inhibition and specific induction of caspases 3/7, 8, and 9. HSV-1 <i>d</i>106S induced a higher ratio of apoptosis-inducing infected cell protein (ICP) 0 to apoptosis-blocking ICP6 than T-VEC. T-VEC was oncolytic for an extended period of time as viral replication continued, which could be partially blocked by the antiviral drug aciclovir. High doses of T-VEC, but not HSV-1 <i>d</i>106S, increased interferon-β mRNA as part of the intrinsic immune response. When markers of immunogenic cell death were assessed, ATP was released more efficiently in the context of T-VEC than HSV-1 <i>d</i>106S infection, whereas HMGB1 was induced comparatively well. Overall, the early oncolytic effect on three different tumour entities was stronger with the non-replicative strain, while the replication-competent virus elicited a stronger innate immune response and more pronounced immunogenic cell death.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"279-294"},"PeriodicalIF":6.4,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13775","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Methyl-supplemented nutrition delays the development of autoimmune disease in pristane-induced murine lupus","authors":"Silviya Bradyanova, Iliyan Manoylov, Gabriela Boneva, Lidiya Kechidzhieva, Andrey Tchorbanov, Kalina Nikolova-Ganeva","doi":"10.1111/imm.13774","DOIUrl":"10.1111/imm.13774","url":null,"abstract":"<p>The aetiology and progression of systemic lupus erythematosus (SLE) resulted from a complex sequence of events generated both from genetic and epigenetic processes. In the current research, the effect of methyl-supplemented nutrition on the development of SLE was studied in the pristane-induced mouse model of the disease. The results clearly demonstrated decreased anti-dsDNA antibody and proteinuria levels, modulation of cytokines and protected renal structures in the group of treated mice. An additional increase in the DNA methylation of mouse B lymphocytes was also observed. The beneficial effect of the diet is due to the methyl-containing micronutrients with possible anti-inflammatory and immunomodulating effects on cell proliferation and gene expression. Since these components are responsible for maintaining the physiological methylation level of DNA, the results point to the central role of methylation processes in environmentally triggered lupus. As nutrition represents one of the major epigenetic factors, these micronutrients may be considered novel agents with significant therapeutic outcomes.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"269-278"},"PeriodicalIF":6.4,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-02-29DOI: 10.1111/imm.13772
Yingying Chen, Hui Li, Jie Zhou
{"title":"Early life vaccination reprograms the metabolism and function of myeloid cells in neonates","authors":"Yingying Chen, Hui Li, Jie Zhou","doi":"10.1111/imm.13772","DOIUrl":"10.1111/imm.13772","url":null,"abstract":"<p>Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette-Guérin (BCG) diminished the immunosuppressive function of myeloid-derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single-cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"252-268"},"PeriodicalIF":6.4,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-02-29DOI: 10.1111/imm.13770
Bowen Lou, Manyun Guo, Tao Zheng, Junhui Liu, Chen Wang, Tao Chen, Fangyuan Chen, Xiaojuan Fan, Shanshan Gao, Xiao Liang, Hua Qiang, Lijuan Li, Bo Zhou, Zuyi Yuan, Jianqing She
{"title":"Single-cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor-related myocarditis","authors":"Bowen Lou, Manyun Guo, Tao Zheng, Junhui Liu, Chen Wang, Tao Chen, Fangyuan Chen, Xiaojuan Fan, Shanshan Gao, Xiao Liang, Hua Qiang, Lijuan Li, Bo Zhou, Zuyi Yuan, Jianqing She","doi":"10.1111/imm.13770","DOIUrl":"10.1111/imm.13770","url":null,"abstract":"<p>Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)-associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single-cell RNA sequencing from ICI-related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single-cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD-1 inhibitor therapy who did not develop myocarditis (PD-1 Group); (3) patients during fulminant ICI-related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI-related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single-cell trajectory and cell–cell interaction analysis were performed after scRNA-seq. Bulk-RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI-related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI-related myocarditis. With integrated analysis of scRNA-seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI-related myocarditis. Our study has created a cell atlas of PBMC during ICI-related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI-related myocarditis in continuous exploration.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"235-251"},"PeriodicalIF":6.4,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-02-26DOI: 10.1111/imm.13769
Ying Wang, Gaoyu Liu, Jianye Wang, Pan Zhou, Lijuan Zhang, Qiang Liu, Jie Zhou
{"title":"NRP1 downregulation correlates with enhanced ILC2 responses during IL-33 challenge","authors":"Ying Wang, Gaoyu Liu, Jianye Wang, Pan Zhou, Lijuan Zhang, Qiang Liu, Jie Zhou","doi":"10.1111/imm.13769","DOIUrl":"10.1111/imm.13769","url":null,"abstract":"<p>Group 2 innate lymphoid cells (ILC2s) play critical roles in driving the pathogenesis of allergic airway inflammation. The mechanisms underlying the regulation of ILC2s remain to be fully understood. Here, we identified neuropilin-1 (NRP1) as a surface marker of ILC2s in response to IL-33 stimulation. NRP1 was abundantly expressed in ILC2s from lung under steady state, which was significantly reduced upon IL-33 stimulation. ILC2s with high expression of NRP1 (NRP1<sup>high</sup>) displayed lower response to IL-33, as compared with NRP1<sup>low</sup> ILC2s. Transcriptional profiling and flow cytometric analysis showed that downregulation of AKT–mTOR signalling participated in the diminished functionality of NRP1<sup>high</sup> ILC2s. These observations revealed a potential role of NRP1 in ILC2s responses under allergic inflammatory condition.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"226-234"},"PeriodicalIF":6.4,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-02-25DOI: 10.1111/imm.13765
Qihang Wu, Han Mao, Zhengting Jiang, Dong Tang
{"title":"Tumour-associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy","authors":"Qihang Wu, Han Mao, Zhengting Jiang, Dong Tang","doi":"10.1111/imm.13765","DOIUrl":"10.1111/imm.13765","url":null,"abstract":"<p>Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 3","pages":"343-361"},"PeriodicalIF":6.4,"publicationDate":"2024-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imm.13765","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139969209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Psychological stress to ovalbumin peptide-specific T-cell receptor transgenic mice impairs the suppressive ability of type 1 regulatory T cell","authors":"Xiaoyu Liu, Xuejie Xu, Yun Liao, Wenkai Yao, Xiaorui Geng, Xianhai Zeng, Xizhuo Sun, Aifa Tang, Pingchang Yang","doi":"10.1111/imm.13767","DOIUrl":"10.1111/imm.13767","url":null,"abstract":"<p>Numerous diseases of the immune system can be traced back to the malfunctioning of the regulatory T cells. The aetiology is unclear. Psychological stress can cause disruption to the immune regulation. The synergistic effects of psychological stress and immune response on immune regulation have yet to be fully understood. The intention of this study is to analyse the interaction between psychological stress and immune responses and how it affects the functional status of type 1 regulatory T (Tr1) cells. In this study, ovalbumin peptide T-cell receptor transgenic mice were utilised. Mice were subjected to restraint stress to induce psychological stress. An airway allergy murine model was established, in which a mouse strain with RING finger protein 20 (Rnf20)-deficient CD4<sup>+</sup> T cells were used. The results showed that concomitant exposure to restraint stress and immune response could exacerbate endoplasmic reticulum stress in Tr1 cells. Corticosterone was responsible for the elevated expression of X-box protein-1 (XBP1) in mouse Tr1 cells after exposure to both restraint stress and immune response. XBP1 mediated the effects of corticosterone on inducing Rnf20 in Tr1 cells. The reduction of the interleukin-10 expression in Tr1 cells was facilitated by Rnf20. Inhibition of Rnf20 alleviated experimental airway allergy by restoring the immune regulatory ability of Tr1 cells. In conclusion, the functions of Tr1 cells are negatively impacted by simultaneous exposure to psychological stress and immune response. Tr1 cells' immune suppressive functions can be restored by inhibiting Rnf20, which has the translational potential for the treatment of diseases of the immune system.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 2","pages":"210-225"},"PeriodicalIF":6.4,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139746533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NK92 cells and peripheral blood NK cells respond oppositely upon dasatinib treatment","authors":"Fengqi Li, Zhongyi Wang, Dongpeng Zheng, Zhaojun Pang, Chunjing Feng, Yue Ma, Ce Yang, Xueren Li, Shouchun Peng, Zichuan Liu, Xin Mu","doi":"10.1111/imm.13768","DOIUrl":"10.1111/imm.13768","url":null,"abstract":"<p>Natural killer (NK) cell is a valuable tool for immunotherapy in cancer treatment, both the cultured cell line NK92 and primary NK cells are widely studied and used in research and clinical trials. Clinical observations witnessed the improvement of patients' NK cells in terms of cell counts and cytotoxic activity upon dasatinib treatment, an approved drug for chronic myeloid leukaemia and Ph<sup>+</sup> acute lymphocytic leukaemia. Several studies supported the clinical observations, yet others argued a detrimental effect of dasatinib on NK cells. Due to the complex conditions in different studies, the definite influence of dasatinib on NK92 and primary NK cells remains to be settled. Here, we used a well-defined in vitro system to evaluate the effects of dasatinib on NK92 cells and peripheral blood (PB)-NK cells. By co-culturing NK cells with dasatinib to test the cell counts and target cell-killing activities, we surprisingly found that the chemical influenced oppositely on these two types of NK cells. While dasatinib suppressed NK92 cell proliferation and cytotoxic activity, it improved PB-NK-killing tumour cells. RNA sequencing analysis further supported this finding, uncovering several proliferating and cytotoxic pathways responding invertedly between them. Our results highlighted an intrinsic difference between NK92 and PB-NK cells and may build clues to understand how dasatinib interacts with NK cells in vivo.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 1","pages":"163-177"},"PeriodicalIF":6.4,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunologyPub Date : 2024-02-15DOI: 10.1111/imm.13766
Masaya Koganesawa, Daniel F. Dwyer, Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sachin Samuchiwal, Hayashi Hiroaki, Airi Nishida, Thomas I. Hirsch, Patrick J. Brennan, Mark Puder, Barbara Balestrieri
{"title":"Pla2g5 contributes to viral-like-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment","authors":"Masaya Koganesawa, Daniel F. Dwyer, Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sachin Samuchiwal, Hayashi Hiroaki, Airi Nishida, Thomas I. Hirsch, Patrick J. Brennan, Mark Puder, Barbara Balestrieri","doi":"10.1111/imm.13766","DOIUrl":"10.1111/imm.13766","url":null,"abstract":"<p>Macrophages expressing group V phospholipase A<sub>2</sub> (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated <i>Pla2g5</i><sup><i>flox/flox</i></sup> mice, deleted <i>Pla2g5</i> by using the <i>Cx3cr1</i><sup><i>cre</i></sup> transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated <i>Pla2g5</i><sup><i>flox/flox</i></sup>;<i>Cx3cr1</i><sup><i>cre/+</i></sup> BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated <i>Pla2g5</i><sup><i>flox/flox</i></sup>;<i>Cx3cr1</i><sup><i>cre/+</i></sup> BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, <i>Pla2g5</i><sup><i>flox/flox</i></sup>;<i>Cx3cr1</i><sup><i>cre/+</i></sup> mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging <i>Pla2g5</i><sup><i>flox/flox</i></sup>;<i>Cx3cr1</i><sup><i>cre/+</i></sup> mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (<i>Ffar1</i>)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation.</p>","PeriodicalId":13508,"journal":{"name":"Immunology","volume":"172 1","pages":"144-162"},"PeriodicalIF":6.4,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}