Cutting edge: Divergent cell-specific functions of MyD88 for inflammatory responses and organ injury in septic peritonitis

The Journal of Immunology : Official Journal of the American Association of Immunologists
Petra GaisBernhard Holzmann

Abstract

Although global MyD88 deficiency attenuates lethal inflammation in sepsis, cell-specific functions of MyD88 remain largely unknown. Using mice with selective expression of MyD88 in myeloid cells (Myd88(MYEL)), we show that, during polymicrobial septic peritonitis, both myeloid and nonmyeloid cells contribute to systemic inflammation, whereas myeloid cell MyD88 was sufficient to fully establish the peritoneal cytokine response. Importantly, Myd88(MYEL) mice developed markedly aggravated liver injury that was linked to impaired upregulation of cellular inhibitor of apoptosis protein 2 and an excessive production of TNF-α. Upregulation of inducible cAMP early repressor (ICER), a known transcriptional repressor of the Tnfa gene, was impaired in Myd88(MYEL) mice. Moreover, Myd88(MYEL) mice showed enhanced transcription of the Tnfa gene and an excessive production of CCL3, which is also negatively regulated by ICER, but they had normal levels of CXCL1, which is expressed in an ICER-independent manner. Together, these findings suggest a novel protective role for nonmyeloid cell MyD88 in attenuating liver injury during septic peritonitis.

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Citations

Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Christian WohnBjörn E Clausen
Feb 17, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mallory L PaynichKatherine L Knight
Jan 18, 2014·European Journal of Immunology·Luciana BerodTim Sparwasser
Mar 2, 2013·Current Opinion in Critical Care·Michael BauerMichael Trauner
May 10, 2020·European Journal of Immunology·Agnès Garcias LópezKatharina Lahl
Nov 19, 2014·European Journal of Immunology·Catharina Arnold-SchraufTim Sparwasser
Feb 15, 2019·Frontiers in Immunology·Jasper RipOdilia B J Corneth
Apr 18, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sara E JonesKatherine L Knight
Jul 30, 2020·ELife·Jaba GamrekelashviliFlorian P Limbourg

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