Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation

Research output: Contribution to journalArticle

Standard

Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. / Vogl, Thomas; Stratis, Athanasios; Wixler, Viktor; Völler, Tom; Thurainayagam, Sumita; Jorch, Selina K.; Zenker, Stefanie; Dreiling, Alena; Chakraborty, Deblina; Fröhling, Mareike; Paruzel, Peter; Wehmeyer, Corinna; Hermann, Sven; Papantonopoulou, Olympia; Geyer, Christiane; Loser, Karin; Schäfers, Michael; Ludwig, Stephan; Stoll, Monika; Leanderson, Tomas; Schultze, Joachim L.; König, Simone; Pap, Thomas; Roth, Johannes.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1852-1866.

Research output: Contribution to journalArticle

Harvard

Vogl, T, Stratis, A, Wixler, V, Völler, T, Thurainayagam, S, Jorch, SK, Zenker, S, Dreiling, A, Chakraborty, D, Fröhling, M, Paruzel, P, Wehmeyer, C, Hermann, S, Papantonopoulou, O, Geyer, C, Loser, K, Schäfers, M, Ludwig, S, Stoll, M, Leanderson, T, Schultze, JL, König, S, Pap, T & Roth, J 2018, 'Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1852-1866. https://doi.org/10.1172/JCI89867

APA

Vogl, T., Stratis, A., Wixler, V., Völler, T., Thurainayagam, S., Jorch, S. K., ... Roth, J. (2018). Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. Journal of Clinical Investigation, 128(5), 1852-1866. https://doi.org/10.1172/JCI89867

CBE

Vogl T, Stratis A, Wixler V, Völler T, Thurainayagam S, Jorch SK, Zenker S, Dreiling A, Chakraborty D, Fröhling M, Paruzel P, Wehmeyer C, Hermann S, Papantonopoulou O, Geyer C, Loser K, Schäfers M, Ludwig S, Stoll M, Leanderson T, Schultze JL, König S, Pap T, Roth J. 2018. Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. Journal of Clinical Investigation. 128(5):1852-1866. https://doi.org/10.1172/JCI89867

MLA

Vancouver

Author

Vogl, Thomas ; Stratis, Athanasios ; Wixler, Viktor ; Völler, Tom ; Thurainayagam, Sumita ; Jorch, Selina K. ; Zenker, Stefanie ; Dreiling, Alena ; Chakraborty, Deblina ; Fröhling, Mareike ; Paruzel, Peter ; Wehmeyer, Corinna ; Hermann, Sven ; Papantonopoulou, Olympia ; Geyer, Christiane ; Loser, Karin ; Schäfers, Michael ; Ludwig, Stephan ; Stoll, Monika ; Leanderson, Tomas ; Schultze, Joachim L. ; König, Simone ; Pap, Thomas ; Roth, Johannes. / Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1852-1866.

RIS

TY - JOUR

T1 - Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation

AU - Vogl, Thomas

AU - Stratis, Athanasios

AU - Wixler, Viktor

AU - Völler, Tom

AU - Thurainayagam, Sumita

AU - Jorch, Selina K.

AU - Zenker, Stefanie

AU - Dreiling, Alena

AU - Chakraborty, Deblina

AU - Fröhling, Mareike

AU - Paruzel, Peter

AU - Wehmeyer, Corinna

AU - Hermann, Sven

AU - Papantonopoulou, Olympia

AU - Geyer, Christiane

AU - Loser, Karin

AU - Schäfers, Michael

AU - Ludwig, Stephan

AU - Stoll, Monika

AU - Leanderson, Tomas

AU - Schultze, Joachim L.

AU - König, Simone

AU - Pap, Thomas

AU - Roth, Johannes

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/ S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

AB - Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/ S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

U2 - 10.1172/JCI89867

DO - 10.1172/JCI89867

M3 - Article

VL - 128

SP - 1852

EP - 1866

JO - Journal of Clinical Investigation

T2 - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -