PMID- 38178102 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240116 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 25 IP - 1 DP - 2024 Jan 4 TI - Age-dependent inflammatory response is altered in an ex vivo model of bacterial pneumonia. PG - 15 LID - 10.1186/s12931-023-02609-w [doi] LID - 15 AB - BACKGROUND: Aging is associated with an increased incidence and mortality of Pseudomonas aeruginosa-induced pneumonias. This might be partly due to age-dependent increases in inflammatory mediators, referred to as inflamm-aging and a decline in immune functions, known as immunosenescence. Still, the impact of dysregulated immune responses on lung infection during aging is poorly understood. Here, we aimed to mimic inflamm-aging using ex vivo precision-cut lung slices (PCLS) and neutrophils - as important effector cells of innate immunity - from young and old mice and investigated the influence of aging on inflammation upon infection with P. aeruginosa bacteria. METHODS: Murine PCLS were infected with the P. aeruginosa standard lab strain PAO1 and a clinical P. aeruginosa isolate D61. After infection, whole-transcriptome analysis of the tissue as well as cytokine expression in supernatants and tissue lysates were performed. Responses of isolated neutrophils towards the bacteria were investigated by quantifying neutrophil extracellular trap (NET) formation, cytokine secretion, and analyzing expression of surface activation markers using flow cytometry. RESULTS: Inflamm-aging was observed by transcriptome analysis, showing an enrichment of biological processes related to inflammation, innate immune response, and chemotaxis in uninfected PCLS of old compared with young mice. Upon P. aeruginosa infection, the age-dependent pro-inflammatory response was even further promoted as shown by increased production of cytokines and chemokines such as IL-1beta, IL-6, CXCL1, TNF-alpha, and IL-17A. In neutrophil cultures, aging did not influence NET formation or cytokine secretion during P. aeruginosa infection. However, expression of receptors associated with inflammatory responses such as complement, adhesion, phagocytosis, and degranulation was lower in neutrophils stimulated with bacteria from old mice as compared to young animals. CONCLUSIONS: By using PCLS and neutrophils from young and old mice as immunocompetent ex vivo test systems, we could mimic dysregulated immune responses upon aging on levels of gene expression, cytokine production, and receptor expression. The results furthermore reflect the exacerbation of inflammation upon P. aeruginosa lung infection as a result of inflamm-aging in old age. CI - (c) 2023. The Author(s). FAU - Sommer, Charline AU - Sommer C AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. FAU - Reamon-Buettner, Stella Marie AU - Reamon-Buettner SM AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. FAU - Niehof, Monika AU - Niehof M AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. FAU - Hildebrand, Christina Beatrix AU - Hildebrand CB AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. AD - Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. AD - Institute of Functional Anatomy, Charite - Universitatsmedizin Berlin, Philippstr. 11, Berlin, 10117, Germany. FAU - Braun, Armin AU - Braun A AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. FAU - Sewald, Katherina AU - Sewald K AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. FAU - Dehmel, Susann AU - Dehmel S AD - Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. susann.dehmel@item.fraunhofer.de. AD - Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Member of Fraunhofer CIMD, Hannover, Germany. susann.dehmel@item.fraunhofer.de. AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. susann.dehmel@item.fraunhofer.de. FAU - Brandenberger, Christina AU - Brandenberger C AD - Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) research network, Hannover, Germany. christina.brandenberger@charite.de. AD - Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. christina.brandenberger@charite.de. AD - Institute of Functional Anatomy, Charite - Universitatsmedizin Berlin, Philippstr. 11, Berlin, 10117, Germany. christina.brandenberger@charite.de. LA - eng PT - Journal Article DEP - 20240104 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Cytokines) RN - 0 (Chemokines) SB - IM MH - Animals MH - Mice MH - *Pneumonia, Bacterial MH - Lung/microbiology MH - Cytokines/metabolism MH - Chemokines/metabolism MH - Neutrophils/metabolism MH - Inflammation/metabolism MH - Pseudomonas aeruginosa MH - *Pseudomonas Infections/microbiology PMC - PMC10765774 OTO - NOTNLM OT - Inflamm-aging OT - Neutrophils OT - Precision-cut lung slices OT - Pseudomonas aeruginosa COIS- The authors declare no competing interests. EDAT- 2024/01/05 00:43 MHDA- 2024/01/08 06:42 PMCR- 2024/01/04 CRDT- 2024/01/04 23:45 PHST- 2023/02/09 00:00 [received] PHST- 2023/11/14 00:00 [accepted] PHST- 2024/01/08 06:42 [medline] PHST- 2024/01/05 00:43 [pubmed] PHST- 2024/01/04 23:45 [entrez] PHST- 2024/01/04 00:00 [pmc-release] AID - 10.1186/s12931-023-02609-w [pii] AID - 2609 [pii] AID - 10.1186/s12931-023-02609-w [doi] PST - epublish SO - Respir Res. 2024 Jan 4;25(1):15. doi: 10.1186/s12931-023-02609-w.