The miR-183/96/182 Cluster Regulates Trigeminal Ganglion Sensory Neurons’ Response to Pseudomonas aeruginosa Infection

Pathogen–host interaction plays key roles in the pathogenesis of infectious diseases. The miR-183/96/182 cluster (miR-183C) is highly expressed in trigeminal ganglion (TG) sensory neurons (SNs) and modulates corneal response to Pseudomonas aeruginosa (PA) infection. To uncover the molecular mechanisms of miR-183C modulating the interactions of PA and TG SN, we employed the miR-183C conventional knockout (KO) or sensory neuron-specific (SNS) conditional (C)KO mouse models. Trigeminal ganglion (TG) SNs were isolated for neurite growth and branching analyses. Neuropeptide and chemokine production by TG SNs in response to PA infection was studied by ELISA assays. Key target genes of miR-183C were validated by target luciferase reporter assays. Our data showed that the total neurite length and number of branches per TG SN were decreased in the CKO vs. WT mice, and in the male vs. female WT mice. PA infection of TG SN induced the production and secretion of CX3CL1 and substance P (sP); this response was significantly enhanced in miR-183C KO vs. WT mice. Antagonists to Toll-like receptor (TLR)4 and/or formyl peptide receptor (FPR)1 inhibited PA-induced responses. Target luciferase reporter assays confirmed that genes encoding TLR4 and FPR1, as well as NRP1—a repulsive axon guidance receptor, TAC1—the precursor gene of sP, CX3CL1 and ADAM10, a metalloproteinase involved in the production of soluble CX3CL1, were direct targets of miR-183C. These data suggest that PA directly activates TG SNs and induces chemokine and neuropeptide production/secretion through interactions with TLR4 and FPR1. miR-183C modulates this process by targeting a collection of key genes involved in axon guidance/projection, chemokine and neuropeptide biogenesis and receptors mediating PA-induced activation.