Docosahexaenoic acid inhibits both NLRP3 inflammasome assembly and JNK-mediated mature IL-1ß secretion in 5-fluorouracil-treated MDSC: implication in cancer treatment.

ABSTRACT

Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1ß secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1ß is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1ß sustains tumor growth recovery in 5-FU-treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anticancer and anti-inflammatory properties, which could improve 5-FU chemotherapy. Here, we demonstrate that DHA inhibits 5-FU-induced IL-1ß secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1ß concentration and tumor recurrence in 5-FU-treated tumor-bearing mice. Treatment with 5-FU led to JNK activation through ROS production in MDSC. JNK inhibitor SP600125 as well as DHA-mediated JNK inactivation decreased IL-1ß secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to ß-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through ß-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1ß release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1ß form. Finally, we found a negative correlation between DHA content in plasma and the induction of caspase-1 activity in HLA-DR- CD33+ CD15+ MDSC of patients treated with 5-FU-based chemotherapy, strongly suggesting that our data are clinical relevant. Together, these data provide new insights on the regulation of IL-1ß secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.