Deletion of MyD88 in T‐Cells Worsens Cardiac Pathology Through Enhanced T‐Cell Survival and Induction of Cardiac Fibrosis
Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti‐inflammatory therapies have shown success. Damage associated molecular patterns (DAMPs) released in the heart activate myeloid cells through the adaptor “Myeloid differentiation primary response 88” (MyD88). This signaling cascade promotes cardiac antigen presentation to activate helper T‐cells. Once activated, T‐cells then infiltrate the heart and bind to VCAM‐1 on cardiac fibroblasts, (CFB), transforming them to myofibroblasts which coordinate cardiac fibrosis. MyD88 is also expressed in T‐cells, yet whether it is pro or anti‐inflammatory is less explored, and evidence suggests is context dependent. To investigate the role of T‐cell MyD88 in HF, we reconstituted Tcra‐/‐ mice, normally protected from HF induced by transaortic constriction (TAC), with WT or Myd88‐/‐ Type 1 helper T‐cells (Th1) in the onset of TAC. Surprisingly, we found that mice receiving Myd88‐/‐ Th1 cells showed increased cardiac T‐cells and fibrosis compared to mice receiving WT cells. We hypothesized that T‐cell MyD88 regulates cardiac T‐cell recruitment and survival, and as a result subsequent cardiac fibrosis. We found that Myd88‐/‐ Th1 cells exhibited increased survival in vitro determined by real time imaging of propidium iodide incorporation, as well as in vivo by performing competitive survival studies in which Tcra‐/‐ mice received equal WT CD45.1 Th1 cells and Myd88‐/‐ CD45.2 Th1 cells. Myd88‐/‐ Th1 cells also induced higher CFB α‐smooth muscle actin staining when cultured together, as well as bound more frequently to CFB and immobilized VCAM‐1. Together these data demonstrate that MyD88 limits T‐cell mediated cardiac fibrosis by regulating T‐cell survival, as well as by dampening T‐cell/fibroblast interactions. We identify novel role for T‐cell MyD88 in cardiac inflammation that may be modulated in HF..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
The FASEB Journal - 36(2022) |
| Beteiligte Personen: |
Bayer, Abraham L. [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© 2022 Federation of American Societies for Experimental Biology |
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| Umfang: |
1 |
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| doi: |
10.1096/fasebj.2022.36.S1.R3436 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Heart failure (HF) is a leading cause of death worldwide, associated with cardiac and systemic inflammation. However, no anti‐inflammatory therapies have shown success. Damage associated molecular patterns (DAMPs) released in the heart activate myeloid cells through the adaptor “Myeloid differentiation primary response 88” (MyD88). This signaling cascade promotes cardiac antigen presentation to activate helper T‐cells. Once activated, T‐cells then infiltrate the heart and bind to VCAM‐1 on cardiac fibroblasts, (CFB), transforming them to myofibroblasts which coordinate cardiac fibrosis. MyD88 is also expressed in T‐cells, yet whether it is pro or anti‐inflammatory is less explored, and evidence suggests is context dependent. To investigate the role of T‐cell MyD88 in HF, we reconstituted Tcra‐/‐ mice, normally protected from HF induced by transaortic constriction (TAC), with WT or Myd88‐/‐ Type 1 helper T‐cells (Th1) in the onset of TAC. Surprisingly, we found that mice receiving Myd88‐/‐ Th1 cells showed increased cardiac T‐cells and fibrosis compared to mice receiving WT cells. We hypothesized that T‐cell MyD88 regulates cardiac T‐cell recruitment and survival, and as a result subsequent cardiac fibrosis. We found that Myd88‐/‐ Th1 cells exhibited increased survival in vitro determined by real time imaging of propidium iodide incorporation, as well as in vivo by performing competitive survival studies in which Tcra‐/‐ mice received equal WT CD45.1 Th1 cells and Myd88‐/‐ CD45.2 Th1 cells. Myd88‐/‐ Th1 cells also induced higher CFB α‐smooth muscle actin staining when cultured together, as well as bound more frequently to CFB and immobilized VCAM‐1. Together these data demonstrate that MyD88 limits T‐cell mediated cardiac fibrosis by regulating T‐cell survival, as well as by dampening T‐cell/fibroblast interactions. We identify novel role for T‐cell MyD88 in cardiac inflammation that may be modulated in HF. | ||
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