Manuka honey activates the aryl hydrocarbon receptor: Implications for skin inflammation.

Manuka honey (MH) is a complex nutritional material with antimicrobial, antioxidant and anti-inflammatory activity. We have previously shown that MH down regulates IL-4-induced CCL26 expression in immortalized keratinocytes. As MH contains potential ligands of the Aryl Hydrocarbon Receptor (AHR), a key regulator of skin homeostasis, we hypothesize that this effect is mediated via AHR activation. Here, we treated HaCaT cell lines, either stable transfected with an empty vector (EV-HaCaT) or in which AHR had been stable silenced (AHR-silenced HaCaT); or primary normal human epithelial keratinocytes (NHEK) with 2% MH for 24 h. This induced a 15.4-fold upregulation of CYP1A1 in EV-HaCaTs, which was significantly reduced in AHR-silenced cells. Pre-treatment with the AHR antagonist CH223191 completely abrogated this effect. Similar findings were observed in NHEK. In vivo treatment of the Cyp1a1Cre x R26ReYFP reporter mice strain's skin with pure MH significantly induced CYP1A1 expression compared with Vaseline. Treatment of HaCaT with 2% MH significantly decreased baseline CYP1 enzymatic activity at 3 and 6 h but increased it after 12 h, suggesting that MH may activate the AHR both through direct and indirect means. Importantly, MH downregulation of IL-4-induced CCL26 mRNA and protein was abrogated in AHR-silenced HaCaTs and by pre-treatment with CH223191. Finally, MH significantly upregulated FLG expression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, both in vitro and in vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation of FLG expression. These results have potential clinical implications for atopic diseases and beyond.

Guardians of the barrier: Microbiota engage AHR in keratinocytes to mantain skin homeostasis.

The skin barrier is critical in ensuring homeostasis, yet factors influencing its development, repair, and maintenance are ill-defined. In this issue of Cell Host & Microbe, Uberoi et al. demonstrate the skin microbiota's role in maintaining barrier integrity via AHR signaling in keratinocytes, which has implications for skin disease management.

Pathogenesis and treatment of psoriasis: exploiting pathophysiological pathways for precision medicine.

Psoriasis is a common, chronic inflammatory skin disease associated with multi-system manifestations including arthritis and obesity. Our knowledge of the aetiology of the condition, including the key genomic, immune and environmental factors, has led to the development of targeted, precision therapies that alleviate patient morbidity. This article reviews the key pathophysiological pathways and therapeutic targets and highlights future areas of interest in psoriasis research.

The reliability of red flags in spinal cord compression.

BACKGROUND: Acute low back pain is a common cause for presentation to the emergency department (ED). Since benign etiologies account for 95% of cases, red flags are used to identify sinister causes that require prompt management. OBJECTIVES: We assessed the effectiveness of red flag signs used in the ED to identify spinal cord and cauda equine compression. PATIENTS AND METHODS: It was a retrospective cohort study of 206 patients with acute back pain admitted from the ED. The presence or absence of the red flag symptoms was assessed against evidence of spinal cord or cauda equina compression on magnetic resonance imaging (MRI). RESULTS: Overall, 32 (15.5%) patients had compression on MRI. Profound lower limb neurologic examination did not demonstrate a statistically significant association with this finding. The likelihood ratio (LR) for bowel and bladder dysfunction (sensitivity of 0.65 and specificity of 0.73) was 2.45. Saddle sensory disturbance (sensitivity of 0.27 and specificity of 0.87) had a LR of 2.11. When both symptoms were taken together (sensitivity of 0.27 and specificity of 0.92), they gave a LR of 3.46. CONCLUSIONS: The predictive value of the two statistically significant red flags only marginally raises the clinical suspicion of spinal cord or cauda equina compression. Effective risk stratification of patients presenting to the ED with acute back pain is crucial; however, this study did not support the use of these red flags in their current form.

Refinement of the locus for distal hereditary motor neuronopathy VII (dHMN-VII) and exclusion of candidate genes.

Distal hereditary motor neuronopathy type seven (dHMN-VII) is an autosomal dominant condition characterized by distal muscular atrophy associated with unilateral or bilateral vocal cord paralysis. We previously mapped the dHMN-VII locus to chromosome 2q14 using a genome-wide linkage scan in a single large pedigree. Here we have performed more detailed microsatellite saturation analysis and also evaluated two new affected individuals not described in the original study. We have significantly refined the extent of the disease locus and show that two distinct regions of chromosome 2q14.2, comprising 9.2 Mb and 4.3 Mb separated by an unusual double recombination event, cosegregate with the disease phenotype. The proximal linked region is now defined by markers D2S3038-D2S160, and the distal region by D2S2970-D2S2969. Sequencing of 15 candidate genes within the critical interval has not yet revealed any pathogenic mutations. Inspection of genomic databases indicates that this refinement of the critical interval by 8.4 Mb reduces the number of candidate genes from approximately 400 to approximately 100.