Abstract
Coordination among multiple signaling pathways ensures an appropriate immune response, where a signaling pathway may impair or augment another signaling pathway. Here, we report a negative feedback regulation of signaling through the key innate immune mediator MyD88 by inflammasome-activated caspase-1. NLRP3 inflammasome activation impaired agonist- or infection-induced TLR signaling and cytokine production through the proteolytic cleavage of MyD88 by caspase-1. Site-specific mutagenesis was used to identify caspase-1 cleavage site within MyD88 intermediary segment. Different cleavage site location within MyD88 defined the functional consequences of MyD88 cleavage between mouse and human cells. LPS/monosodium urate–induced mouse inflammation model corroborated the physiological role of this mechanism of regulation, that could be reversed by chemical inhibition of NLRP3. While Toll/interleukin-1 receptor (TIR) domain released by MyD88 cleavage additionally contributed to the inhibition of signaling, Waldenström’s macroglobulinemia associated MyD88L265P mutation is able to evade the caspase-1-mediated inhibition of MyD88 signaling through the ability of its TIRL265P domain to recruit full length MyD88 and facilitate signaling. The characterization of this mechanism reveals an additional layer of innate immunity regulation.
Highlights
The innate immune response is essential for the defense against pathogens and supports the repair of tissue damage via sensing danger signals
Since MyD88 is a central adaptor in Toll-like receptors (TLRs) and IL-1 receptor (IL-1R) signaling, we aimed to investigate whether there is an additional mechanism of regulation involving MyD88 that could restrict the excessive signaling
The activation of NLRP3 inflammasome but not pyroptosis was responsible for the decreased production of tumor necrosis factor-a (TNFa) and IL-6
Summary
The innate immune response is essential for the defense against pathogens and supports the repair of tissue damage via sensing danger signals. Precise regulation of the innate immune response is of great importance in maintaining a balance between adequate defense against pathogens and damage caused due to excessive inflammation. MyD88 couples TIRdomain mediated receptor activation via its TIR domain to signaling kinases that are recruited through death domains (DD) of MyD88 into a myddosomal complex [6]. A point mutation within TIR domain of MyD88 can lead to the constitutive activity of MyD88 that is a survival signal for proliferation in DLBC lymphoma cells, in Waldenstrom’s macroglobulinemia [8,9,10]. Inhibition of mutated MyD88 mediated signaling, on the other hand, can prevent replication of cancer cells, inhibition of MyD88 signaling may be important for cancer, autoimmune disease and response to infection. The role of MyD88 has been first identified more than 20 years ago [11], some mechanisms of its negative regulation remain unknown
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