IRF7 Modulates Inflammatory Pain Through Upregulating IFNbeta in Mice Trigeminal Ganglion

Despite the high global burden of chronic pain, current therapeutic options remain limited. The transcription factor IRF7, primarily known for its role in immunity, has emerged as a potential regulator of nociception. However, a significant knowledge gap exists regarding its peripheral functions and mechanisms in orofacial pain. This study investigates the hypothesis that IRF7 and its downstream effector IFNβ act within the trigeminal ganglion (TG) to modulate orofacial pain pathways. The expression levels of IRF7 and IFNβ in the TG were evaluated in a mouse model of orofacial inflammatory pain. IRF7 was knocked down in the TG using AAV-mediated shRNA delivery. The functional interaction between IRF7 and IFNβ was tested through applying exogenous IFNβ, blocking its receptor, and performing a key rescue experiment to test if IFNβ reconstitution could reverse the effects of IRF7 loss. Inflammatory pain led to a significant upregulation of IRF7 and IFNβ in the TG neuron. IRF7 knockdown alleviated mechanical allodynia, reduced spinal neuronal activation, and suppressed pro-inflammatory mediators (IL-6 and NLRP3). Exogenous IFNβ exacerbated pain hypersensitivity and the nociceptive effects was attenuated by IFNAR antagonism. IFNβ rescued the pain modulation deficits resulting from IRF7 knockdown. Supplementing exogenous IFNβ rescued the pain modulation deficits resulting from IRF7 knockdown in an inflammatory pain condition. Our findings demonstrate that the peripheral IRF7–IFNβ axis drives inflammatory pain pathogenesis, identifying a novel therapeutic target for chronic pain management.