2. Academic Validation
  3. CXCL9 and CXCL10 Induce Expression of Nociceptive Ion Channels in Primary Sensory Neurons in Models of HIV-Associated Distal Sensory Polyneuropathy

CXCL9 and CXCL10 Induce Expression of Nociceptive Ion Channels in Primary Sensory Neurons in Models of HIV-Associated Distal Sensory Polyneuropathy

  • Int J Mol Sci. 2026 Jan 4;27(1):523. doi: 10.3390/ijms27010523.
Rebecca Warfield 1,  Jake A Robinson 2,  Stephen Baak 3,  Rachel M Podgorski 1,  Tara A Gabor 1,  Maurizio Caocci 3,  Meng Niu 4,  Andrew D Miller 5,  Howard S Fox 4,  Tricia H Burdo 3
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology, and Inflammation, Center for NeuroVirology and Gene Editing, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 2 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Medicine, Rutgers Institute of Translational Medicine and Science, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 89 French Street, New Brunswick, NJ 08901, USA.
  • 4 Department of Neurological Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 5 Department of Population Medicine and Diagnostic Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
PMID: 41516395 DOI: 10.3390/ijms27010523
Abstract

HIV-associated distal sensory polyneuropathy (HIV-DSP) remains prevalent even in the antiretroviral therapy (ART) era. Previously, we identified the upregulation of nociceptive ion channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in the dorsal root ganglia (DRG) of simian immunodeficiency virus (SIV)-infected ART-treated macaques. To investigate upstream mechanisms, we performed bulk RNA-seq and pathway analysis on DRGs from uninfected, SIV-infected, and SIV-infected/ART macaques. SIV Infection drove strong activation of upstream regulators of interferon γ (IFNγ) and lipopolysaccharide (LPS). Although ART reduced overall IFNγ and LPS pathway activity, the IFNγ-inducible chemokines C-X-C motif chemokine ligand (CXCL)9 and CXCL10 remained significantly upregulated. To determine whether these chemokines influence TRPV1/TRPA1 expression, we treated induced pluripotent stem cell-derived peripheral sensory neurons (iPSC-PSNs) with CXCL9 and CXCL10, which induced a significant increase in TRPV1 but not TRPA1 expression. In parallel experiments, IFNγ but not LPS stimulated monocyte-derived macrophages (MDMs) to release CXCL9 and CXCL10. Conditioned media from IFNγ-treated MDMs modestly increased TRPV1 expression in iPSC-PSNs, and pharmacological inhibition of CXCR3, the receptor of CXCL9/10, did not reduce this effect. Together, these data indicate that persistent IFNγ-driven CXCL9/10 signaling may be one contributor to nociceptor sensitization underlying HIV-DSP, even in the presence of ART.

Keywords

HIV; SIV; neuroinflammation; neuropathy.

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