NR4A1 mediates PRRSV-induced ileal injury in piglets by transcriptional regulation of NLRP3.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection poses a serious threat to swine health, with ileal injury representing a key pathological manifestation. However, the role of nuclear receptor NR4A1 in PRRSV-induced ileal damage remains unclear. This study investigated the relationship between PRRSV-induced ileal injury and nuclear receptor NR4A1. Our results demonstrate that PRRSV infection induces inflammatory responses, leading to reduced growth performance and intestinal damage in piglets. Mechanistically, PRRSV-triggered inflammation causes pyroptosis in ileal cells, as evidenced by: (1) elevated serum levels of metabolic markers including diamine oxidase, D-lactate and intestinal fatty acid-binding protein; and (2) upregulated transcriptional expression of pyroptosis-related genes,including-NOD-like receptor family pyrin domain-containing 3 (NLRP3), interleukin-1β (IL1β), interleukin-18 (IL18), apoptosis-associated speck-like protein containing a CARD (ASC), gasdermin D (GSDMD), and caspase-1 (CASP1). These findings confirm the crucial role of pyroptosis in PRRSV-mediated ileal inflammatory injury. Importantly, we found that PRRSV activates the nuclear receptor NR4A1, which in turn upregulates the expression of NLRP3 in the pyroptosis pathway. This study provides the first evidence that nuclear receptor NR4A1 mediates PRRS-induced pyroptosis in piglet ileum through transcriptional regulation of NLRP3.