Myeloid cell-derived proteases produce a proinflammatory form of IL-37 that signals via IL-36 receptor engagement
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2022Access:
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Sullivan, G.P. and Davidovich, P. and Muñoz-Wolf, N. and Ward, R.W. and Hernandez Santana, Y.E. and Clancy, D.M. and Gorman, A. and Najda, Z. and Turk, B. and Walsh, P.T. and Lavelle, E.C. and Martin, S.J., Myeloid cell-derived proteases produce a proinflammatory form of IL-37 that signals via IL-36 receptor engagement, Science immunology, 7, 78, 2022, eade5728Download Item:
Abstract:
Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1β. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S-processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R-/- animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.
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Science immunology;7;
78;
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Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1126/sciimmunol.ade5728Metadata
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