Teaching an old pathway new tricks: Targeting BTK to block NLRP3

The immune system relies on the rapid, pattern-based innate immune response and the slower, antigen-specific adaptive immune response to fight pathogens. On the innate side, the inflammasome is a multiprotein complex that, upon NLRP3 activation, is constructed to allow production of interleukin-1β (IL-1β). When regulated appropriately it plays important antipathogen roles, and when improperly regulated it causes autoinflammatory cryopyrin-associated periodic syndromes, including Muckle-Wells syndrome (MWS). On the adaptive side, B cells are a fundamental component of the adaptive immune response, playing important antipathogen roles by multiple strategies, including opsonization of pathogens. Mutations in Bruton’s tyrosine kinase (BTK), a key signaling molecule in B cells, are known to cause X-linked agammaglobulinemia (XLA) with a near absence of both B cells and immunoglobulin. In this paper by Liu et al., the two arms of the immune response are drawn together, connecting these pathways. They began with a proteomic screen to identify regulators of NLRP3 and identified BTK. They blocked BTK using both chemical (ibrutinib, a BTK inhibitor) and genetic (Btk−/− mice and XLA patients) means, showing in each case that there is inhibition of IL-1β release. They were then able to demonstrate that BTK has direct interactions with components of the inflammasome, including NLRP3. NLRP3 activation stimuli (both chemical and pathogen-derived, including S. aureus toxins) had reduced ability to produce IL-1β release in cells with genetic BTK deficiency. An in vivo mouse model of S. aureus, controlled in part at baseline by IL-1β, demonstrated worse disease progression in ibrutinib-treated mice. In vitro ibrutinib blockade of BTK in peripheral blood mononuclear cells (PBMC) from MWS patients showed reduced secretion of IL-1β. Last, they were able to demonstrate reduced IL-1β secretion with ex vivo NLRP3 stimulation in PBMC from oncology patients undergoing ibrutinib treatment. This paper has implications for the immunodeficiency seen in XLA, which has a clinical phenotype that extends beyond infections that can be linked to B cell deficiency alone. More fundamentally, this paper presents the potential for an orthogonal strategy to target the inflammasome, and inflammation more generally, by exploring the use of BTK as a novel regulator.

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