Signal inhibitory receptor on leukocytes-1 (SIRL-1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus... Show moreSignal inhibitory receptor on leukocytes-1 (SIRL-1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus Staphylococcus secrete SIRL-1-engaging factors. By screening a library of single-gene transposon mutants in Staphylococcus aureus, we identified these factors as phenol-soluble modulins (PSMs). PSMs are amphipathic alpha-helical peptides involved in multiple aspects of staphylococcal virulence and physiology. They are cytotoxic and activate the chemotactic formyl peptide receptor 2 (FPR2) on immune cells. Human cathelicidin LL-37 is also an amphipathic alpha-helical peptide with antimicrobial and chemotactic activities, structurally and functionally similar to alpha-type PSMs. We demonstrate that alpha-type PSMs from multiple staphylococcal species as well as human cathelicidin LL-37 activate SIRL-1, suggesting that SIRL-1 recognizes alpha-helical peptides with an amphipathic arrangement of hydrophobicity, although we were not able to show direct binding to SIRL-1. Upon rational peptide design, we identified artificial peptides in which the capacity to ligate SIRL-1 is segregated from cytotoxic and FPR2-activating properties, allowing specific engagement of SIRL-1. In conclusion, we propose staphylococcal PSMs and human LL-37 as a potential new class of natural ligands for SIRL-1. Show less
Rumpret, M.; Richthofen, H.J. von; Linden, M. van der; Westerlaken, G.H.A.; Ormeno, C.T.; Low, T.Y.; ... ; Meyaard, L. 2021
Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector... Show moreSignal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. In this study, we identify S100 proteins as SIRL-1 ligands. S100 proteins are composed of two calcium-binding domains. Various S100 proteins are damage-associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL-1 recognizes individual calcium-binding domains of all tested S100 proteins. Blocking SIRL-1 on human neutrophils enhanced S100 protein S100A6-induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL-1. Taken together, SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs. This may help limit tissue damage induced by activated neutrophils. Show less
Borne, P. van den; Rygiel, T.P.; Hoogendoorn, A.; Westerlaken, G.H.A.; Boon, L.; Quax, P.H.A.; ... ; Meyaard, L. 2014
We longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a... Show moreWe longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a low plasma viral load (<15,000 copies/mL), whereas others could not (>50,000 copies/mL). Before HAART was initiated, plasma viral load was similar. After TI, the numbers of CD8(+) T cells increased more in individuals without viral control, whereas individuals maintaining a low viral load showed a more pronounced increase in HIV-specific CD8(+) T-cell numbers. No differences were seen in the number or percentage of cytokine-producing HIV-1-specific CD4(+) T cells, or in proliferative capacity of T cells. Four weeks after TI, the magnitude of the total HIV-1-specific CD8(+) T-cell response (IFN-gamma(+) and/or IL-2(+) and/or CD107a(+)) was significantly higher in individuals maintaining viral control. Degranulation contributed more to the overall CD8(+) T-cell response than cytokine production. Whether increased T-cell functionality is a cause or consequence of low viral load remains to be elucidated. Show less
