Left ventricle- and skeletal muscle-derived fibroblasts exhibit a differential inflammatory and metabolic responsiveness to interleukin-6

Matz, Isabell; Pappritz, Kathleen; Springer, Jochen; Linthout, Sophie Van

doi:10.3389/fimmu.2022.947267

Cited by 3 publications

(7 citation statements)

References 62 publications

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“…Since cFB are recognized as important inflammatory supporter cells ( 13 , 16 , 17 , 24 ) and senescent cells are able to switch into a senescence-associated secretory phenotype (SASP) with inflammatory potential ( 33 , 34 ), cellular senescence ( Figure 1 ) and the inflammatory capacity of male and female cFB was analyzed ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Given the relevance of the cardiosplenic axis in cardiac fibrosis on the one hand ( 20 ) and the potential of cFB to attract different monocyte subsets depending on the inflammatory milieu on the other hand ( 17 , 24 ), we next investigated the CCL2, CCL7, and Cx3CL1 protein concentration in cFB-derived supernatant ( Figures 3A , B ).…”

Section: Resultsmentioning

confidence: 99%

“…LV fibrosis is caused by excessive deposition of ECM components, whereby cFB are the main producers as well as regulators ( 13 , 37 ). Beyond ECM production, cFB act as important modulators of inflammation ( 13 , 16 , 17 , 24 ). So far, only a few studies have simultaneously examined age- and sex-related differences in cardiac fibrosis ( 38 – 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…Murine cFB were obtained via outgrowth culture as previously described ( 17 , 24 ). In brief, the LV was cut in small pieces and fixed in 12-well culture plates.…”

Section: Methodsmentioning

confidence: 99%

“…Own data support the relevance of these chemokines, since ablation of CX3CR1 resulted in an increased level of CCL2 accompanied by higher numbers of monocytes/macrophages in the heart of viral-infected mice ( 23 ). Accumulating evidence shows that cFB influence the migration of splenic pro- (Ly6C high ) and anti- (Ly6C low ) inflammatory monocytes, depending on the inflammatory milieu ( 17 , 24 ). However, the impact of sex and age in this context has not been investigated so far.…”

Section: Introductionmentioning

confidence: 99%

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Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis

Pappritz,

Puhl,

Matz

et al. 2023

Front. Cardiovasc. Med.

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BackgroundAge and sex are prominent risk factors for heart failure and determinants of structural and functional changes of the heart. Cardiac fibroblasts (cFB) are beyond their task as extracellular matrix-producing cells further recognized as inflammation-supporting cells. The present study aimed to evaluate the impact of sex and age on the inflammatory potential of cFB and its impact on the cardiosplenic axis and cardiac fibrosis.MaterialsLeft ventricles (LV) of 3- and 12-months old male and female C57BL/6J mice were harvested for immunohistochemistry, immunofluorescence and cFB outgrowth culture and the spleen for flow cytometry. LV-derived cFB and respective supernatants were characterized.ResultsLV-derived cFB from 3-months old male mice exhibited a higher inflammatory capacity, as indicated by a higher gene expression of CC-chemokine ligand (CCL) 2, and CCL7 compared to cFB derived from 3-months old female mice. The resulting higher CCL2/chemokine C-X3-C motif ligand (Cx3CL1) and CCL7/Cx3CL1 protein ratio in cell culture supernatants of 3-months old male vs. female cFB was reflected by a higher migration of Ly6Chigh monocytes towards supernatant from 3-months old male vs. female cFB. In vivo a lower ratio of splenic pro-inflammatory Ly6Chigh to anti-inflammatory Ly6Clow monocytes was found in 3-months old male vs. female mice, suggesting a higher attraction of Ly6Chigh compared to Ly6Clow monocytes towards the heart in male vs. female mice. In agreement, the percentage of pro-inflammatory CD68+ CD206− macrophages was higher in the LV of male vs. female mice at this age, whereas the percentage of anti-inflammatory CD68+ CD206+ macrophages was higher in the LV of 3-months old female mice compared to age-matched male animals. In parallel, the percentage of splenic TGF-β+ cells was higher in both 3- and 12-months old female vs. male mice, as further reflected by the higher pro-fibrotic potential of female vs. male splenocytes at both ages. In addition, female mice displayed a higher total LV collagen content compared to age-matched male mice, whereby collagen content of female cFB was higher compared to male cFB at the age of 12-months.ConclusionAge- and sex-dependent differences in cardiac fibrosis and inflammation are related to age- and sex-dependent variations in the inflammatory properties of cardiac fibroblasts.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Murine cFB were obtained via outgrowth culture as previously described ( 17 , 24 ). In brief, the LV was cut in small pieces and fixed in 12-well culture plates.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis

Pappritz,

Puhl,

Matz

et al. 2023

Front. Cardiovasc. Med.

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Myocardial fibrosis from the perspective of the extracellular matrix: Mechanisms to clinical impact

Lunde,

Rypdal,

Van Linthout

et al. 2024

Matrix Biology

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Cardiac fibroblasts and mechanosensation in heart development, health and disease

et al. 2022

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The sensing of mechanical tissue properties is a process related to cell differentiation, maturation and pathology in multicellular organs such as the heart.-Remodelling of the cardiac extracellular matrix, which occurs as a consequence of a pathological stimulus, induces changes in the mechanical properties of the myocardium. -Variations in the mechanical properties of the myocardium are related to the activation of pro-fibrotic cells (so-called myofibroblasts). -Mechanical cues can potentiate pro-fibrotic humoral signalling.-The identification of molecular pathways involved in mechanosensation of myofibroblasts facilitates the identification of therapeutic targets that can reverse mechanically induced pathological activation. -The possibility that interfering with mechanical cues in vivo might result in cardiac regeneration opens new therapeutic avenues in cardioprotection.

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Left ventricle- and skeletal muscle-derived fibroblasts exhibit a differential inflammatory and metabolic responsiveness to interleukin-6

Cited by 3 publications

References 62 publications

Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis

Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis

Myocardial fibrosis from the perspective of the extracellular matrix: Mechanisms to clinical impact

Cardiac fibroblasts and mechanosensation in heart development, health and disease

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