Chemokine-chemokine receptor (CKR) interactions are traditionally described by a two-step/two-site mechanism that details the major contact points between chemokine ligands and CKRs leading to ligand recognition and receptor activation. Chemokine recognition site 1 (CRS1) encompasses interactions between the CKR N-terminus and the globular chemokine core. Chemokine recognition site 2 (CRS2) includes interactions between the unstructured chemokine N-terminus and the binding pocket of the receptor. The two-step/two-site paradigm has been an adequate framework to study the intricacies of chemokine:CKR interactions, but emerging studies highlight the limitations of this model. Here, we present studies of CRS2 interactions between the chemokine CCL20 and its cognate receptor CCR6 driven by the hypothesis that CCL20 interacts with CCR6 as described by the two-step/two-site model. CCL20 is a chemokine with an unusually short N-terminus of 5 residues (NH -ASNFD), compared to the average length of 10 residues for chemokine ligands. We have investigated how well CCL20 tolerates manipulation of the N-terminus by monitoring binding affinity of variants and their ability to activate the receptor. We show the CCL20 N-terminus tolerates truncation of up to 3 residues, extension by up to 5 additional residues, and point mutations at 4 of 5 positions with minimal loss of binding affinity and minimal impairment in ability to stimulate calcium mobilization, inositol triphosphate accumulation, chemotaxis, and β-arrestin-2 recruitment. Mutation of the fifth residue, aspartate, to alanine or lysine has a dramatic impact on binding affinity for CCR6 and ligand potency. We postulate CCL20 does not activate CCR6 through the canonical two-step/two-site mechanism of CKR activation.
A 56-year-old woman presented with complaints of otalgia with left-sided hearing loss. She reported left tympanic membrane perforation and chronic ear infections secondary to traumatic injury as a child. She also had a history of intermittent otorrhea in the year prior to being seen at the clinic. Tympanometry of the left ear revealed restricted eardrum mobility and large equivalent ear canal volume. Audiometric testing showed a mild sensorineural hearing loss in the right ear and moderately severe mixed hearing loss in the left ear. The patient had a speech reception threshold of 45 dB hearing level (HL) and 88% word recognition at 80 dB HL with her left ear. An otoendoscope was used to examine the patient's left external auditory canal and tympanic membrane, then advanced beyond the annulus and through the tympanic membrane perforation to the middle ear itself. A mass was seen superior to the eustachian tube opening and medial to the manubrium of the malleus (Figure 1). Subsequent computed tomography (CT) imaging revealed abnormal demineralization and lucency in the region of the facial nerve (FN) geniculate ganglion and along the rostral roof of the middle ear (Figure 2A and B). The location of the abnormality visualized by CT corresponded to the location of the mass observed during middle ear exploration. Magnetic resonance imaging (MRI) revealed an enhancing lesion present in the left FN geniculate ganglion region measuring 6 to 7 mm ( Figure 2C and D). The pattern of demineralization present in the CT scan, together with the enhancing lesion observed by MRI, suggested FN hemangioma of the geniculate ganglion. Notably, the patient did not have any symptoms of FN weakness. No surgical intervention was taken; MRI follow-up 6 months later revealed no change in size of the hemangioma. DiscussionGeniculate ganglion hemangiomas (GGHs) are rare, benign vascular tumors of the FN involving the geniculate ganglion. 1 Facial nerve weakness is the most common presentation symptom of these tumors; a systematic review by Oldenburg et al found patients presented with FN palsy in 94% of GGH reported in the literature. Hearing loss and otalgia were less common presentation symptoms, found in 15% and 2% of reported cases, respectively. 2 There is disagreement regarding optimal management of GGH, due in part to the rarity of these lesions. Geniculate ganglion hemangiomas represent 0.7% of all temporal bone tumors, 3 with approximately 130 unique cases reported in the literature. 2,4 The limited research available suggests better outcomes when intervention is taken Figure 1. Otoscopy reveals mass in the middle ear (white arrow). ET indicates eustachian tube opening; JN, Jacobson's nerve; M, manubriumof the malleus.
Background Chemokines represent a superfamily of immune-modulatory small protein molecules that regulate leukocyte migration to inflammatory sites through their chemoattractant and cell signaling properties. This review focuses on the immunological functions of the CCR6 chemokine receptor and is chemokine ligand, CCL20, that contribute to it role in inflammation in human psoriasis. Methods Peer-reviewed relevant articles are searched and selected from 2000 to 2022 using the search engines including PubMed and Google Scholar. Results After selectively reviewing and evaluating over seventy articles, a comprehensive overview on the immunology of CCL20-CCR6 axis in psoriasis and psoriatic arthritis, the X-ray crystal structures of CCL20 monomers, and the potential of developing clinical therapies targeting this axis is summarized. Conclusions Over the past decade, preclinical studies carried out in animal models of psoriasis involving agents targeting CCL20-CCR6 axis have yielded promising results. Other studies that this axis may play a role in a number of other autoimmune diseases, including rheumatoid arthritis, suggesting a rationale for further investigation into this key signaling/migratory pathway.
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