Classification of acute appendicitis (CAA): treatment directed new classification based on imaging (ultrasound, computed tomography) and pathology.

PURPOSE: Acute appendicitis (AA) is amongst the most common causes of acute abdominal pain. In spite of progress based on risk stratifications, "negative" appendectomies are performed in up to 30% of patients whilst the appendix perforates in others. Preoperative classification of AA based on imaging is therefore recommended. The aim was to classify AA based on imaging (ultrasound/US, computed tomography/CT), surgical pathology, and/or histopathology in order to differentiate between complicated and uncomplicated AA. A new classification of acute appendicitis (CAA) shall be illustrated by typical US and CT images and be employed in a diagnostic and therapeutic algorithm. METHODS: Medline, Embase, and the Cochrane Library were searched. Any study after 1970, which investigated clinical scores, pathology, US, CT, magnetic resonance imaging, and treatment of AA, was included. Typical images were taken from the author's image database. RESULTS: Five main types of AA are defined, normal appendix (type 0), nonvisualised appendix (type X), uncomplicated AA (type 1), complicated AA without perforation (type 2), and complicated AA with perforation (type 3). The imaging modality is indicated by an additional letter, e.g., type p3b for free perforation on pathology. Standardised reporting of the appendix evaluation by US and CT is presented, as well as algorithms for AA management. Imaging features indicating imminent perforation, as well as likely recurrence, were both classified as complicated AA. CONCLUSION: Imaging is mandatory in suspected AA. The CAA clearly separates uncomplicated from complicated forms of AA allowing nonoperative management in selected patients with uncomplicated forms of AA.

The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes.

Pairing orphan G protein­coupled receptors (GPCRs) with their cognate endogenous ligands is expected to have a major impact on our understanding of GPCR biology. It follows that the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into the pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as a dualistic uracil nucleotide/cysteinyl leukotriene receptor and by others as inactive toward these stimuli altogether. Whereas regulation of central nervous system myelination by GPR17 is well established, verification of activity of its putative endogenous ligands has proven elusive so far. Herein we report that uracil nucleotides and cysteinyl leukotrienes do not activate human, mouse, or rat GPR17 in various cellular backgrounds, including primary cells, using eight distinct functional assay platforms based on labelfree pathway-unbiased biosensor technologies, as well as canonical second-messenger or biochemical assays. Appraisal of GPR17 activity can neither be accomplished with co-application of both ligand classes, nor with exogenous transfection of partner receptors (nucleotide P2Y12, cysteinyl-leukotriene CysLT1) to reconstitute the elusive pharmacology. Moreover, our study does not support the inhibition of GPR17 by the marketed antiplatelet drugs cangrelor and ticagrelor, previously suggested to antagonize GPR17. Whereas our data do not disagree with a role of GPR17 per se as an orchestrator of central nervous system functions, they challenge the utility of the proposed (ant)agonists as tools to imply direct contribution of GPR17 in complex biologic settings.

A biased ligand for OXE-R uncouples Gα and Gßγ signaling within a heterotrimer.

Differential targeting of heterotrimeric G protein versus ß-arrestin signaling are emerging concepts in G protein-coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either ß-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gßγ but not Gα signaling triggered upon activation of Gα(i)-ßγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gßγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.

D-type prostanoid receptor enhances the signaling of chemoattractant receptor-homologous molecule expressed on T(H)2 cells.

BACKGROUND: Prostaglandin (PG) D(2) is substantially involved in allergic responses and signals through the 7 transmembrane-spanning/G protein-coupled receptors, chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH2), and D-type prostanoid (DP) receptor. OBJECTIVE: Although the proinflammatory function of CRTH2 is well recognized and CRTH2 is hence considered an important emerging pharmacotherapeutic target, the role of the DP receptor in mediating the biological effects of PGD(2) in patients with allergic inflammation has remained unclear. METHODS: The cross-talk of CRTH2 and DP receptors was investigated by using both a recombinant HEK293 cell model and human eosinophils in Ca(2+) mobilization assays, coimmunoprecipitation, Western blotting, radioligand binding, and immunofluorescence. RESULTS: We show that CRTH2 and DP receptors modulate one another's signaling properties and form CRTH2/DP heteromers without altering their ligand-binding capacities. We find that the DP receptor amplifies the CRTH2-induced Ca(2+) release from intracellular stores and coincidentally forfeits its own signaling potency. Moreover, desensitization or pharmacologic blockade of the DP receptor hinders CRTH2-mediated signal transduction. However, CRTH2 internalization occurs independently of the DP receptor. In cells that express both receptors, pharmacologic blockade of Gα(q/11) proteins abolishes the Ca(2+) response to both CRTH2 and DP agonists, whereas inhibition of Gα(i) proteins selectively attenuates the CRTH2-mediated response but not the DP signal. CONCLUSION: Our data demonstrate the capacity of DP receptors to amplify the biological response to CRTH2 activation. Therefore the CRTH2/DP heteromer might not only represent a functional signaling unit for PGD(2) but also a potential target for the development of heteromer-directed therapies to treat allergic diseases.

CT-based patient-specific modeling of glenoid rim defects: a feasibility study.

OBJECTIVE: Reconstruction of glenoid bone defects requires accurate preoperative planning. The purpose of this study is to present a method for quantifying the defect size and generating a 3D model of the bone graft for augmentation by matching the fractured glenoid with the contralateral side. MATERIALS AND METHODS: Ten paired shoulders from five cadavers (subjects: three women and two men; mean age, 85 years) and 60 paired shoulders in 30 patients (controls: nine women and 21 men; mean age, 21 years) were examined using CT to determine bilateral comparability by assessment of the maximum glenoid diameters, surface area, and volume. After creation of a glenoid rim defect in the study group, repeated CT scans were superimposed with the data from the contralateral side. The defect size was quantified and the missing fragment virtually reconstructed. Accuracy was evaluated by comparing the virtually repaired glenoid with the predefect CT scan. RESULTS: There were no significant side-to-side differences in intact shoulders (p < 0.05). After creation of the glenoid defects, there was a mean decrease of 31% in the anteroposterior diameter, 34% in surface area, and 19% in volume. The virtually reconstructed glenoids did not differ significantly from the predefect CT scans. The averaged predefect-to-postdefect difference was 3% for the anteroposterior diameter (R(2) = 0.71), 6% for the surface area (R(2) = 0.82), and 4% for the volume (R(2) = 0.98). CONCLUSION: A precise 3D model of the glenoid bony defect can be generated. The computer simulation provides a virtual model of the bone graft, which may potentially improve arthroscopic bone augmentation.

Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation.

Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients.

Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma.

Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

CT colonography using different reconstruction modi.

OBJECTIVE: Performing computed tomography (CT) colonography, we compared different reconstruction modi for the detection of colorectal polyps. METHODS: The CT data of 48 patients using 16-slice helical CT were analysed in axial slices, virtual-endoscopy and colon-dissection modus. RESULTS: The sensitivity (specificity) for the detection of colonic polyps was 94% (80%) if using "colonic-dissection" tool and 89% (80%) if using "virtual-endoscopy" tool. The difference between the virtual endoscopy and colon dissection, considering polyps up to 4.9 mm, was significant. CONCLUSIONS: Reconstruction software colon dissection improves the sensitivity of CT colonography.

Panoramic X-rays. Comprehensive radiodiagnostics or radiation protection at all costs?

A case report is presented to examine the question of whether a panoramic x-ray in standard projection can be readily replaced by a radiation-reduced projection with shielding of the condylar processes.A female patient with juvenile idiopathic arthritis was examined by a panoramic x-ray and MRI prior to TMJ splinting. The panoramic x-ray in standard projection showed short, atypically-shaped condylar processes with cystic lesions and cortical erosion. The MRI confirmed the TMJ destruction. The condylar processes were shielded on the x-rays taken for a previous orthodontic treatment. Thus TMJ assessment was not done, though it is an integral part of orthodontic radiodiagnostics according to Hirschfelder and other authors. This example of juvenile idiopathic arthritis with TMJ involvement shows that visualization of the condylar processes is indispensable.

Influence of cage design on interbody fusion in a sheep cervical spine model.

OBJECT: The purpose of this study was to compare the characteristics of interbody fusion achieved using an autologous tricortical iliac crest bone graft with those of a cylinder- and a box-design cage in a sheep cervical spine model. This study was designed to determine whether there are differences between three interbody fusion procedures in: 1) ability to preserve postoperative distraction; 2) biomechanical stability; and 3) histological characteristics of intervertebral bone matrix formation. METHODS: Twenty-four sheep underwent C3-4 discectomy and fusion in which the following were used: Group 1, autologous tricortical iliac crest bone graft (eight sheep); Group 2, titanium cylinder-design cage filled with autologous iliac crest bone graft (eight sheep); and Group 3, titanium box-design cage filled with autologous iliac crest graft (eight sheep). Radiography was performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the sheep were killed, and fusion sites were evaluated by obtaining functional radiographs in flexion and extension. Quantitative computerized tomography scans were acquired to assess bone mineral density, bone mineral content, and bone callus volume. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphological and histomorphometric analyses were performed, and polychrome sequential labeling was used to determine the time frame of new bone formation. Over a 12-week period significantly higher values for disc space height and intervertebral angle were shown in cage-treated sheep than in those that received bone graft. Functional radiographic assessment revealed significantly lower residual flexion-extension movement in sheep with the cylinder cage-fixed spines than in those that received bone graft group. The cylinder-design cages showed significantly higher values for bone mineral content, bone callus content, and stiffness in axial rotation and lateral bending than the other cages or grafts. Histomorphometric evaluation and polychrome sequential labeling showed a more progressed bone matrix formation in the cylindrical cage group than in both other groups. CONCLUSIONS: Compared with the tricortical bone graft, both cages showed significantly better distractive properties. The cylindrical cage demonstrated a significantly higher biomechanical stiffness and an accelerated interbody fusion compared with the box-design cage and the tricortical bone graft. The differences in bone matrix formation within both cages were the result of the significantly lower stress shielding on the bone graft by the cylinder-design cage.

Repetitive transarterial chemoembolization (rTACE) of hepatocellular carcinoma: comparisons between an arterial port system and conventional angiographic technique.

PURPOSE: To compare the cost and radiation exposure of repetitive transarterial chemoembolization (rTACE) using percutaneously implantable port system with rTACE using conventional catheterization technique. MATERIALS AND METHODS: In five patients with unresectable hepatocellular carcinoma, three cycles of TACE were performed using conventional technique and six cycles using port. The cumulative cost of material and contrast agent and dose area product (DAP) were compared with the cost and DAP that would be expected if the rTACE was performed conventionally. RESULTS: The cost of material and contrast agent was 1002.6 Euro after three cycles of TACE using conventional technique and six cycles using port, but would be 1111.8 Euro if the nine cycles were performed using conventional technique alone. The rTACE with three cycles using conventional technique and six cycles using port led to approximately 63% of the cumulative DAP that would be expected in rTACE using conventional technique alone. CONCLUSION: In rTACE, the use of percutaneously implantable port system might enable a reduction of cost and radiation exposure.

[Quantitative determination of coronary vascular calcinosis (coronary calcium score) with double-helical CT]. / Quantitative Bestimmung des Koronargefässkalkes (Koronarkalziumscore) mit der Zweizeilenspiral-CT.

Coronary heart disease is a common disease, with the typical characteristic of coronary sclerosis, an abnormal calcification of the heart's blood vessels. The amount of coronary calcification is in direct correlation to the extent of coronary heart disease. With the double-detector-helical-CT it is possible to detect and quantify these calcifications. The correlation of the "Calcium-Scoring" with the results of coronary-angiography, myocardial scintigraphy and clinical findings shows the value of this method of coronary heart diagnostic. False negative results, based on low calcified fatty stenotic plaques and false positive results, based on high calcificated plaques without significant stenosis should be taken into account.

ß-arrestin 2 inhibits proinflammatory chemokine production and attenuates contact allergic inflammation in the skin.

ß-Arrestins participate in G-protein receptor signaling and act as adapter proteins that direct the recruitment, activation, and scaffolding of various cytoplasmic signaling complexes. ß-Arrestin 2-deficient (Arrb2(-/-)) mice show decreased T-cell recruitment into allergic lung tissue but increased neutrophil infiltration into wounded skin. Given these opposing effects in different immune cell subsets, we investigated the role of ß-arrestin 2 in the regulation of contact hypersensitivity responses. We observed significantly increased allergic ear swelling to the obligate contact sensitizers DNFB and FITC in Arrb2(-/-) compared with wild-type mice. Immunohistological analyses revealed strikingly increased neutrophil infiltration with abundant subcorneal pustules in inflamed ear tissue of DNFB-allergic Arrb2(-/-) mice. Experiments involving adoptive transfers of sensitized lymphocytes and bone marrow chimeric mice indicated that ß-arrestin 2 exerts its anti-inflammatory effects predominantly through radioresistant, skin-resident cells in the challenge phase of contact hypersensitivity. As a potential mechanism, we found that primary cultures of ß-arrestin 2-deficient keratinocytes secreted higher levels of neutrophil-attracting chemokines including CXCL1/KC in response to T cell-derived cytokines in vitro. These experimental results support a model in which ß-arrestin 2 inhibits the production of proinflammatory chemokines, which limits the recruitment of myeloid immune cells and thereby attenuates allergic skin inflammation.

A cell-permeable inhibitor to trap Gαq proteins in the empty pocket conformation.

In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Gαq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Gαq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Gα inhibitor to date. Our data show that Gα proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Gα subclasses with cell-permeable inhibitors.

Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist.

Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the "purinergic cluster," has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the Gα(i), Gα(s), and Gα(q) subfamily, as well as ß-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca²âº flux, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS.

PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2.

Prostaglandin H(1) (PGH(1)) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as "anti-inflammatory". Herein we present evidence that PGH(1) is a potent activator of the pro-inflammatory PGD(2) receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca(2+) flux studies reveal that PGH(1) activates CRTH2 as PGH(2), PGD(2) or PGD(1) do. The PGH(1) precursor DGLA and the other PGH(1) metabolites did not display such effect. PGH(1) specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH(1) is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH(1) mediates migration of and Ca(2+) flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH(1) as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.

Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties.

FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.

Arthroscopic soft tissue tenodesis versus bony fixation anchor tenodesis of the long head of the biceps tendon.

BACKGROUND: Currently there are no prospective data available that compare the different tenodesis techniques of the long head of the biceps tendon with regard to their clinical and structural results. HYPOTHESIS: Soft tissue tenodesis provides clinical and structural results equivalent to those of bony fixation anchor tenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fifty-seven patients with arthroscopically proven lesions of the long head of the biceps tendon (LHB) were prospectively included in this study. Thirty patients (7 women, 23 men; mean age, 57.9 years) were treated with an arthroscopic soft tissue tenodesis (STT) and 27 patients (8 women, 19 men; mean age, 61 years) with an arthroscopic bony fixation anchor tenodesis (BFAT). The clinical evaluation included the Constant score as well as a newly developed LHB score (maximum 100 points) that includes evaluation of pain and cramps (maximum 50 points), the patient- and examiner-dependent grading of the cosmetic result (maximum 30 points), and the measurement of elbow flexion strength (maximum 20 points). The integrity of the tenodesis construct was evaluated indirectly by detecting the position of the LHB using magnetic resonance imaging. A proximal intertubercular location of the tendon was judged as an intact tenodesis construct (3 points), a distal intertubercular location as a failure of tenodesis followed by autotenodesis in the sulcus (2 points), and an extratubercular location as a complete failure (1 point). RESULTS: Twenty-four patients (5 women, 19 men; mean age, 58.6 years; mean follow-up, 19.6 months) in the STT group and 20 patients (5 women, 15 men; mean age, 59.1 years; mean follow-up, 22.4 months) in the BFAT group could be evaluated. The overall Constant score did not reveal any significant difference in the STT group (mean, 75.0 points) compared with the BFAT group (mean, 78.3 points) (P > .05). However, the BFAT group showed significantly better results in the LHB score (BFAT mean, 91.8 points vs STT mean, 80.9 points), the examiner-dependent evaluation of the cosmetic result (BFAT mean, 11.3 points vs STT mean, 8.0 points), as well as in the evaluation of the structural integrity of the tenodesis construct (BFAT mean, 2.7 points vs STT mean, 2.2 points) (P < .05). CONCLUSION: When arthroscopic tenodesis of the LHB is indicated, the authors recommend a bony fixation over soft tissue fixation because anchor fixation provides significant advantages concerning the clinical and structural outcome.

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.

The directional migration of neutrophils towards inflammatory mediators, such as chemokines and cannabinoids, occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process. A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB(2) receptor (CB(2)R), but additional modulatory sites distinct from CB(2)R have recently been suggested to impact CB(2)R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB(2)R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB(2)R agonist 2-arachidonoylglycerol (2-AG), while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production. Using HEK293 and HL60 cell lines, along with primary neutrophils, we show that GPR55 and CB(2)R interfere with each other's signaling pathways at the level of small GTPases, such as Rac2 and Cdc42. This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils. Therefore, GPR55 limits the tissue-injuring inflammatory responses mediated by CB(2)R, while it synergizes with CB(2)R in recruiting neutrophils to sites of inflammation.