Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis
The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/8857 |
| _version_ | 1797444940204081152 |
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| author | Alexander B. Sigalov |
| author_facet | Alexander B. Sigalov |
| author_sort | Alexander B. Sigalov |
| collection | DOAJ |
| description | The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA. |
| first_indexed | 2024-03-09T13:18:41Z |
| format | Article |
| id | doaj.art-a409d600df204a1c96ce0751c6142508 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:18:41Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a409d600df204a1c96ce0751c61425082023-11-30T21:32:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316885710.3390/ijms23168857Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental ArthritisAlexander B. Sigalov0SignaBlok, Inc., P.O. Box 4064, Shrewsbury, MA 01545, USAThe triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA.https://www.mdpi.com/1422-0067/23/16/8857triggering receptors expressed on myeloid cellsTREM-1TREM-2inflammationinnate immunitysignal transduction |
| spellingShingle | Alexander B. Sigalov Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis International Journal of Molecular Sciences triggering receptors expressed on myeloid cells TREM-1 TREM-2 inflammation innate immunity signal transduction |
| title | Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis |
| title_full | Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis |
| title_fullStr | Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis |
| title_full_unstemmed | Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis |
| title_short | Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis |
| title_sort | inhibition of trem 2 markedly suppresses joint inflammation and damage in experimental arthritis |
| topic | triggering receptors expressed on myeloid cells TREM-1 TREM-2 inflammation innate immunity signal transduction |
| url | https://www.mdpi.com/1422-0067/23/16/8857 |
| work_keys_str_mv | AT alexanderbsigalov inhibitionoftrem2markedlysuppressesjointinflammationanddamageinexperimentalarthritis |