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Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during Haemophilus parasuis infection.

ABSTRACT: Haemophilus parasuis (H. parasuis) causes exudative inflammation, implying endothelial dysfunction during pathogen infection. However, so far, the molecular mechanism of endothelial dysfunction caused by H. parasuis has not been clarified. By using the transwell-based cell co-culture system, we demonstrate that knocking out resistin in porcine alveolar macrophages (PAMs) dramatically attenuated endothelial monolayer damage caused by H. parasuis. The resistin secreted by PAMs inhibited the expression of the tight junction proteins claudin-5 and occludin rather than the adherens junction protein VE-cadherin in co-cultured porcine aortic endothelial cells (PAECs). Furthermore, we demonstrate that resistin regulated claudin-5 and occludin expression and monolayer PAEC permeability in an LKB1/AMPK/mTOR pathway-dependent manner. Additionally, we reveal that the outer membrane lipoprotein gene lppA in H. parasuis induced resistin expression in PAMs, as deleting lppA reduced resistin expression in H. parasuis-infected PAMs, causing a significant change in LKB1/AMPK/mTOR pathway activity in co-cultured PAECs, thereby restoring tight junction protein levels and endothelial monolayer permeability. Thus, we postulate that the H. parasuis lppA gene enhances resistin production in PAMs, disrupting tight junctions in PAECs and causing endothelial barrier dysfunction. These findings elucidate the pathogenic mechanism of exudative inflammation caused by H. parasuis for the first time and provide a more profound angle of acute exudative inflammation caused by bacteria.

SUBMITTER: Hua K

PROVIDER: S-EPMC9928480 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during Haemophilus parasuis infection.

Hua Kexin K Li Tingting T He Yanling Y Guan Aohan A Chen Liying L Gao Yuan Y Xu Qianshuan Q Wang Haoyu H Luo Rui R Zhao Ling L Jin Hui H

Virulence 20231201 1

Haemophilus parasuis (H. parasuis) causes exudative inflammation, implying endothelial dysfunction during pathogen infection. However, so far, the molecular mechanism of endothelial dysfunction caused by H. parasuis has not been clarified. By using the transwell-based cell co-culture system, we demonstrate that knocking out resistin in porcine alveolar macrophages (PAMs) dramatically attenuated endothelial monolayer damage caused by H. parasuis. The resistin se ...[more]

PMID: 36694280

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Project description:BackgroundHaemophilus parasuis (H. parasuis) is the etiological agent of Glässer's disease in pigs. Currently, the molecular basis of this infection is largely unknown. The innate immune response is the first line of defense against the infectious disease. Systematical analysis on host innate immune response to the infection is important for understanding the pathogenesis of the infectious microorganisms.ResultsA total of 428 differentially expressed (DE) genes were identified in the porcine alveolar macrophages (PAMs) 6 days after H. parasuis infection. These genes were principally related to inflammatory response, immune response, microtubule polymerization, regulation of transcript and signal transduction. Through the pathway analysis, the significant pathways mainly concerned with cell adhesion molecules, cytokine-cytokine receptor interaction, complement and coagulation cascades, toll-like receptor signaling pathway, MAPK signaling pathway, suggesting that the host took different strategies to activate immune and inflammatory response upon H. parasuis infection. The global interactions network and two subnetworks of the proteins encoded by DE genes were analyzed by using STRING. Further immunostimulation analysis indicated that mRNA levels of S100 calcium-binding protein A4 (S100A4) and S100 calcium-binding protein A6 (S100A6) in porcine PK-15 cells increased within 48 h and were sustained after administration of lipopolysaccharide (LPS) and Poly (I:C) respectively. The s100a4 and s100a6 genes were found to be up-regulated significantly in lungs, spleen and lymph nodes in H. parasuis infected pigs. We firstly cloned and sequenced the porcine coronin1a gene. Phylogenetic analysis showed that poCORONIN 1A belonged to the group containing the Bos taurus sequence. Structural analysis indicated that the poCORONIN 1A contained putative domains of Trp-Asp (WD) repeats signature, Trp-Asp (WD) repeats profile and Trp-Asp (WD) repeats circular profile at the N-terminus.ConclusionsOur present study is the first one focusing on the response of porcine alveolar macrophages to H. parasuis. Our data demonstrate a series of genes are activated upon H. parasuis infection. The observed gene expression profile could help screening the potential host agents for reducing the prevalence of H. parasuis and further understanding the molecular pathogenesis associated with H. parasuis infection in pigs.

Project description:BackgroundHaemophilus parasuis (HPS) is an important swine pathogen that causes Glässer's disease, which is characterized by fibrinous polyserositis, meningitis and arthritis. The molecular mechanisms that underlie the pathogenesis of the disease remain poorly understood, particularly the resistance of porcine immune system to HPS invasion. In this study, we investigated the global changes in gene expression in the spleen following HPS infection using the Affymetrix Porcine Genechip.ResultsA total of 931 differentially expressed (DE) transcripts were identified in the porcine spleen 7 days after HPS infection; of these, 92 unique genes showed differential expression patterns based on analysis using BLASTX and Gene Ontology. The DE genes involved in the immune response included genes for inflammasomes (RETN, S100A8, S100A9, S100A12), adhesion molecules (CLDN3, CSPG2, CD44, LGALS8), transcription factors (ZBTB16, SLC39A14, CEBPD, CEBPB), acute-phase proteins and complement (SAA1, LTF, HP, C3), differentiation genes for epithelial cells and keratinocytes (TGM1, MS4A8B, CSTA), and genes related to antigen processing and presentation (HLA-B, HLA-DRB1). Further immunostimulation analyses indicated that mRNA levels of S100A8, S100A9, and S100A12 in porcine PK-15 cells increased within 48 h and were sustained after administration of lipopolysaccharide (LPS) and Poly(I:C) respectively. In addition, mapping of DE genes to porcine health traits QTL regions showed that 70 genes were distributed in 7 different known porcine QTL regions. Finally, 10 DE genes were validated by quantitative PCR.ConclusionOur findings demonstrate previously unrecognized changes in gene transcription that are associated with HPS infection in vivo, and many potential cascades identified in the study clearly merit further investigation. Our data provide new clues to the nature of the immune response in mammals, and we have identified candidate genes that are related to resistance to HPS.

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Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during Haemophilus parasuis infection.

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Resistin secreted by porcine alveolar macrophages leads to endothelial cell dysfunction during <i>Haemophilus parasuis</i> infection.

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