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Alendronate Augments Lipid A–Induced IL-1α Release via Activation of ASC but Not Caspase-11

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Abstract

Nitrogen-containing bisphosphonates (NBPs), such as alendronate (ALN), are anti-bone-resorptive drugs that have inflammatory side effects. We previously reported that ALN augmented lipid A–induced interleukin (IL)-1β production and NOD-like receptor pyrin domain-containing-3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)-dependent cell death. The present study aimed to examine whether ALN augments lipid A–induced IL-1α release and necroptosis, which is induced by the activation of receptor-interacting protein kinase (RIPK) 3. Treatment of J774.1 cells with ALN augmented lipid A–induced IL-1α release, which was not inhibited by Ac-IETD-CHO, a caspase-8 inhibitor. ALN also activated mixed lineage kinase domain-like (MLKL), a key mediator of the necroptosis pathway, and upregulated the expression of caspase-11, a lipid A receptor. GSK′872, a RIPK3 inhibitor, suppressed the ALN-upregulated expression of caspase-11 and augmented lipid A–induced caspase-8 activation. Moreover, ALN induced the release of NLRP3 and ASC into culture supernatants. GSK′872, but not Ac-IETD-CHO, reduced the ALN-induced release of NLRP3, but not ASC, into culture supernatants, and reduced ALN-induced cell death, but not ALN-induced LDH release. Antibodies against NLRP3 and ASC upregulated caspase-11 expression in the cytosol by inhibiting ALN-induced cell death. However, pretreating cells with an antibody against ASC, but not NLRP3, before ALN addition also inhibited lipid A–induced IL-1α release. Pretreating cells with an antibody against caspase-11 before the addition of ALN or lipid A did not downregulate lipid A–induced production of IL-1α. Taken together, our findings suggest that ALN augments lipid A–induced IL-1α release via activation of ASC, but not caspase-11.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by a Grant-in-Aid for Scientific Research from the Ohu University School of Dentistry, including the President’s discretionary expense.

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Riyoko Tamai: Conceptualization, validation, formal analysis, investigation, data curation, writing, visualization, supervision, project administration, and funding acquisition. Izumi Mashima: Funding acquisition. Yusuke Kiyoura: Funding acquisition.

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Tamai, R., Mashima, I. & Kiyoura, Y. Alendronate Augments Lipid A–Induced IL-1α Release via Activation of ASC but Not Caspase-11. Inflammation 44, 2132–2141 (2021). https://doi.org/10.1007/s10753-021-01489-w

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