KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis
Abstract Background Fibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, d...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-01-01
|
| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-018-1783-9 |
| _version_ | 1818526121529966592 |
|---|---|
| author | Mark R. Tanner Michael W. Pennington Satendra S. Chauhan Teresina Laragione Pércio S. Gulko Christine Beeton |
| author_facet | Mark R. Tanner Michael W. Pennington Satendra S. Chauhan Teresina Laragione Pércio S. Gulko Christine Beeton |
| author_sort | Mark R. Tanner |
| collection | DOAJ |
| description | Abstract Background Fibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other’s phenotypes. Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated TEM cells. In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and TEM cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA. Methods We used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic TEM cells. We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS. Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies. Results We show that the interactions of FLS from rats with CIA and of rat TEM cells are regulated by KCa1.1 and Kv1.3. Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate TEM cell proliferation and migration, and inhibiting Kv1.3 on TEM cells reduces TEM cells’ ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion. Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA. Conclusions Our results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and TEM cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA. |
| first_indexed | 2024-12-11T06:18:33Z |
| format | Article |
| id | doaj.art-96a71378e38d4196b2cdb3f6084d13a6 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-11T06:18:33Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-96a71378e38d4196b2cdb3f6084d13a62022-12-22T01:17:54ZengBMCArthritis Research & Therapy1478-63622019-01-0121112110.1186/s13075-018-1783-9KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritisMark R. Tanner0Michael W. Pennington1Satendra S. Chauhan2Teresina Laragione3Pércio S. Gulko4Christine Beeton5Department of Molecular Physiology and Biophysics, Baylor College of MedicinePeptides International, Inc.Peptides International, Inc.Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount SinaiDepartment of Molecular Physiology and Biophysics, Baylor College of MedicineAbstract Background Fibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other’s phenotypes. Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated TEM cells. In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and TEM cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA. Methods We used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic TEM cells. We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS. Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies. Results We show that the interactions of FLS from rats with CIA and of rat TEM cells are regulated by KCa1.1 and Kv1.3. Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate TEM cell proliferation and migration, and inhibiting Kv1.3 on TEM cells reduces TEM cells’ ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion. Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA. Conclusions Our results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and TEM cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA.http://link.springer.com/article/10.1186/s13075-018-1783-9Synovial fibroblastImmunomodulationCell interactionsDual therapyAutoimmunity |
| spellingShingle | Mark R. Tanner Michael W. Pennington Satendra S. Chauhan Teresina Laragione Pércio S. Gulko Christine Beeton KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis Arthritis Research & Therapy Synovial fibroblast Immunomodulation Cell interactions Dual therapy Autoimmunity |
| title | KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis |
| title_full | KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis |
| title_fullStr | KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis |
| title_full_unstemmed | KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis |
| title_short | KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis |
| title_sort | kca1 1 and kv1 3 channels regulate the interactions between fibroblast like synoviocytes and t lymphocytes during rheumatoid arthritis |
| topic | Synovial fibroblast Immunomodulation Cell interactions Dual therapy Autoimmunity |
| url | http://link.springer.com/article/10.1186/s13075-018-1783-9 |
| work_keys_str_mv | AT markrtanner kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis AT michaelwpennington kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis AT satendraschauhan kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis AT teresinalaragione kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis AT perciosgulko kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis AT christinebeeton kca11andkv13channelsregulatetheinteractionsbetweenfibroblastlikesynoviocytesandtlymphocytesduringrheumatoidarthritis |