ATF5 activates LPAR5 to enhance macrophage pro-inflammatory responses to exacerbate rheumatoid arthritis.

Macrophages (Mφ) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) through their ability to polarize into different functional phenotypes. Even though lysophosphatidic acid receptor 5 (LPAR5) has been implicated in regulating Mφ in inflammatory diseases, its functional role in controlling Mφ remains unclear under the condition of RA. LPAR5 expression was significantly increased in synovial Mφ from RA patients, and correlated positively with severe pathological progression in RA patients. Adeno-associated virus-mediated specific knockdown of LPAR5 in Mφ blocked PI3K/AKT signaling to inhibit pro-inflammatory polarization of Mφ in DBA/1 mice with collagen-induced arthritis. Dysregulation of LPAR5 in RA was associated with activating transcription factor 5 (ATF5)-mediated transcriptional activation. Overexpression of LPAR5 reversed the restriction of pro-inflammatory responses of Mφ by ATF5 knockdown by activating the PI3K/AKT signaling. ATF5 activated the PI3K/AKT signaling pathway through LPAR5, and the activation of PI3K/AKT signaling further promoted ATF5 expression through a positive feedback loop, amplifying pro-inflammatory responses of Mφ. Overall, our findings support that ATF5/LPAR5/PI3K/AKT positive feedback signaling amplifies pro-inflammatory responses of Mφ to promote RA progression. Targeting the ATF5/LPAR5/PI3K/AKT cascade may emerge as a potential therapeutic strategy to alleviate RA.