Biology subjects

Jankowski, M. P.

Publications and source records attributed to Jankowski, M. P..

8 recordsLinked to original sources

bioRxiv2024

Identification of a Neuroimmune Circuit that Regulates Allergic Inflammation in the Esophagus

Eosinophilic esophagitis is a chronic food antigen-driven allergic inflammatory disease associated with symptoms involving the nervous system such as refractory pain. Yet, the role of the nervous system in disease pathogenesis has not received much attention. Herein, we demonstrate that allergen exposure evokes pain-like behavior in association with increased nociceptor signaling and transcriptional responses in dorsal root ganglia. NaV1.8+ sensory nerves were found traveling along the length of the esophagus, organized in distinct bundles adjacent to the basal epithelium, with beta III-tubulin+ sensory nerves distributed more distal to the lumen. Targeted deletion of Il4ra in NaV1.8+ neurons impeded allergen-induced increases in nerve innervation density. Furthermore, Il4ra-/-NaV1.8 mice had diminished allergen-induced allergic inflammation in the esophagus including eosinophilia and transcription of pro-inflammatory genes. Translational studies revealed extensive myelinated nerve innervation in the human esophagus, which was increased in patients with eosinophilic esophagitis. Taken together, these data indicate that allergic inflammation is associated with an increase in non-evoked pain, esophageal nerve density, altered sensitivity of sensory neurons, and transcriptional changes in dorsal root ganglia. These finding identify a type 2 neuroimmune circuit that involves the interplay of allergen-induced IL-4 receptor-dependent DRG responses that modify esophageal end-organ inflammatory responses.

immunology↗

bioRxiv2024

The intersection of endocrine signaling and neuroimmune communication regulates neonatal nociception

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates. We found that local GH treatment inhibited neonatal inflammatory myalgia but appeared to do so through a unique signal transducer and activator of transcription (STAT) dependent pathway within sensory neurons. The STAT1 transcription factor appeared to regulate peripheral inflammation itself by modulation of monocyte chemoattractant protein 1 (MCP1) release from sensory neurons. Data suggests that STAT1 upregulation, downstream of GH signaling, contributes to neonatal nociception during muscle inflammation through a novel neuroimmune loop involving cytokine release from primary afferents. Results could uncover new ways to treat muscle pain and inflammation in neonates. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/605393v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@18b0bdorg.highwire.dtl.DTLVardef@fb5ee9org.highwire.dtl.DTLVardef@114179aorg.highwire.dtl.DTLVardef@19979b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Sex specific role of RNA-binding protein, AUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury

Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. I/R injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity due to I/R may be due to sex specific gene expression in the DRGs and distinct upregulation of growth factors and cytokines in the affected muscles. In order to determine how these unique gene expression programs may be established in a sex dependent manner in a model that more closely mimics clinical scenarios, we utilized a newly developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries to the forelimb and compared behavioral results to unbiased and targeted screening strategies in male and female DRGs. Several distinct proteins were found to be differentially expressed in male and female DRGs, including AU-rich element RNA binding protein (AUF1), which is known to regulate gene expression. Nerve specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, while overexpression of AUF1 in male DRG neurons increased some pain-like responses. Further, AUF1 knockdown was able to specifically inhibit repeated I/R induced gene expression in females but not males. Data suggests that RNA binding proteins like AUF1 may underlie the sex specific effects on DRG gene expression that modulate behavioral hypersensitivity after repeated I/R injury. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.

neuroscience↗

bioRxiv2023

Schwann cells modulate nociception in neurofibromatosis 1

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome Neurofibromatosis 1 (NF1), even when tumors are absent. Schwann cells (SC) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in mice. In mouse models, animals show afferent and behavioral hypersensitivity when SC, but not neurons, lack Nf1. Importantly, hypersensitivity corresponds with SC-specific upregulation of mRNA encoding glial cell line derived neurotrophic factor (GDNF), independent of the presence of tumors. Neuropathic pain-like behaviors in the NF1 mice were inhibited by either chemogenetic silencing of SC calcium or by systemic delivery of GDNF targeting antibodies. Together, these findings suggest that Nf1 loss in SCs causes mechanical pain by influencing adjacent neurons and, data may identify cell-specific treatment strategies to ameliorate pain in individuals with NF1. Graphical AbstractGDNF released from Schwann cells acts on sensory neurons leading to mechanical hypersensitivity and pain-like behaviors in preclinical models of NF1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/533004v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d17177org.highwire.dtl.DTLVardef@706f56org.highwire.dtl.DTLVardef@19db1ccorg.highwire.dtl.DTLVardef@3e28d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming

The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to early life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling. The p75 neurotrophic factor receptor (NTR) was an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" was long lasting in females and could be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/528015v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@117ad6eorg.highwire.dtl.DTLVardef@17b4188org.highwire.dtl.DTLVardef@10b4d9borg.highwire.dtl.DTLVardef@1142094_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Early life nociception is influenced by peripheral growth hormone signaling

A number of cellular systems work in concert to modulate nociceptive processing in the periphery, but the mechanisms that regulate neonatal nociception may be distinct compared to adults. Our previous work indicated a relationship between neonatal hypersensitivity and growth hormone (GH) signaling. Here, we explored the peripheral mechanisms by which GH modulated neonatal nociception under normal and injury conditions (incision). We found that GH receptor signaling in primary afferents maintains a tonic inhibition of peripheral hypersensitivity. After injury, a macrophage dependent displacement of injury-site GH was found to modulate neuronal transcription at least in part via serum response factor regulation. A single GH injection into the injured hindpaw muscle effectively restored available GH signaling to neurons and prevented acute pain-like behaviors, primary afferent sensitization, and neuronal gene expression changes. GH treatment also inhibited long-term somatosensory changes observed after repeated peripheral insult. Results may indicate a novel mechanism of neonatal nociception. Significance statementAlthough it is noted that mechanisms of pain development in early life are unique compared to adults, little research focuses on neonatal-specific peripheral mechanisms of nociception. This gap is evident in the lack of specialized care for infants following an injury including surgeries. This report evaluates how distinct cellular systems in the periphery including the endocrine, immune and nervous systems work together to modulate neonatal-specific nociception. We uncovered a novel mechanism by which muscle injury induces a macrophage-dependent sequestration of peripheral growth hormone that effectively removes its normal tonic inhibition of neonatal nociceptors to promote acute pain-like behaviors. Results indicate a possible new strategy for treatment of neonatal post-surgical pain.

neuroscience↗

bioRxiv2019

A role for peripheral GDNF signaling in ischemic myalgia development

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPR). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor 1 (GFR1) in DRGs. Here we report that increased GDNF/GFR1 signaling to sensory neurons from ischemia/reperfusion affected muscle modulated nociceptive-like behaviors, increased EPRs, and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased CREB/CREB-binding protein mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may play an important dual role in nociception and sympathetic reflexes and could provide a novel therapeutic target for treating complications from ischemic injuries.

neuroscience↗

bioRxiv2019

Single cell q-PCR derived expression profiles of identified sensory neurons

Sensory neurons are chemically and functionally heterogeneous and this heterogeneity has been examined extensively over the last several decades. These studies have employed a variety of different methodologies, including anatomical, electrophysiological and molecular approaches. Recent studies using next generation sequencing techniques have examined the transcriptome of single sensory neurons. Although, these reports have provided a wealth of exciting new information on the heterogeneity of sensory neurons, correlation with functional types is lacking. Here, we employed retrograde tracing of cutaneous and muscle afferents to examine the variety of mRNA expression profiles of individual, target-specific sensory neurons. In addition, we used an ex vivo skin/nerve/DRG/ spinal cord preparation to record and characterize the functional response properties of individual cutaneous sensory neurons that were then intracellularly labeled with fluorescent dyes, recovered from dissociated cultures and analyzed for gene expression. We found that by using single cell qPCR techniques and a limited set of genes, we can identify transcriptionally distinct groups. We have also used calcium imaging and single cell qPCR to determine the correlation between levels of mRNA expression and functional protein expression and how functional properties correlated with the different transcriptional groups. These studies show that although transcriptomics does map to functional types, within any one functional subgroup, there are highly variable patterns of gene expression. Thus, studies that rely on the expression pattern of one or a few genes as a stand in for physiological experiments, runs a high risk of data misinterpretation with respect to function. Significance statementExpression profiles of unidentified sensory neurons have been recently studied using RNASeq techniques. Here, we utilize a multifactorial approach to target identified cutaneous and muscle afferents to examine expression and functional levels of specific high priority candidate genes using ex vivo electrophysiology, Ca2+ imaging, and single cell qPCR. Using this methodology, we were able to identify specific groups of neurons with distinct functional properties that corresponded to unique transcriptional profiles. This represents the first attempt to relate neuronal phenotype with levels of gene expression in single identified afferents and highlights the importance of combining functional analysis with transcriptomics.

neuroscience↗