The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage

The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention.

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“…Many authors have shown the impact of chemokine receptor complexes (dimers/oligomers) on chemokine functions (Table ). Hauser et al.…”

Section: Chemokine Receptor Dimerization/oligomerization: a Potentialmentioning

confidence: 99%

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Martínez-Muñoz

Villares

Rodrı́guez-Fernández

et al. 2018

Journal of Leukocyte Biology

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“…; Del Prete et al. ), and published data implicate each of these cells in one or more of the various pathological sequelae induced by O 3 . For example, the use of gadolinium chloride to suppress macrophage function or nedocromil sodium to stabilize mast cell function significantly reduced the ability of O 3 to increase lung permeability and to cause lung inflammation (Kleeberger et al.…”

Section: Introductionmentioning

confidence: 96%

“…; Del Prete et al. ). Because Ccrl2 influences leukocyte migration in the absence of G protein signaling, Ccrl2 is subclassified as an atypical chemokine receptor within the chemokine receptor family (Bachelerie et al.…”

Section: Introductionmentioning

confidence: 98%

“…; Del Prete et al. ; Monaghan ). While the majority of receptors within the chemokine receptor family initiate leukocyte trafficking via G protein‐dependent signaling (Bachelerie et al.…”

Section: Introductionmentioning

confidence: 99%

“…Second, a recent study by Del Prete et al. () reported that Ccrl2 influenced the ability of chemokine (C‐X‐C motif) receptor 2 (CXCR2), the receptor for KC and MIP‐2 (Konrad and Reutershan ), to promote neutrophil migration. This observation is relevant to our current study since we previously reported that CXCR2‐deficient mice had fewer bronchoalveolar lavage fluid (BALF) neutrophils (Johnston et al.…”

Section: Introductionmentioning

confidence: 99%

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Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone

et al. 2017

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Inhalation of ozone (O3), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O3. Furthermore, each of these aforementioned cells express chemokine (C‐C motif) receptor‐like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O3‐induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O3, we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O3. To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl‐β‐methylcholine chloride (respiratory system resistance) in wild‐type and mice genetically deficient in Ccrl2 (Ccrl2‐deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O3. In air‐exposed mice, BALF chemerin was greater in Ccrl2‐deficient as compared to wild‐type mice. O3 increased BALF chemerin in mice of both genotypes, yet following O3 exposure, BALF chemerin was greater in Ccrl2‐deficient as compared to wild‐type mice. O3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O3‐induced lung pathology.

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Gene Expression Profiling in Pediatric Appendicitis

Dhillon,

Kortbeek,

Baghela

et al. 2024

JAMA Pediatr

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ImportanceAppendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery.ObjectiveTo provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population.Design, Setting, and ParticipantsThe Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children’s Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study.ExposureSA, PA, or nonappendicitis abdominal pain.Main Outcomes and MeasuresBlood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics.ResultsSeventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified.ConclusionsThis study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.

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The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage

Cited by 79 publications

References 51 publications

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Remodeling our concept of chemokine receptor function: From monomers to oligomers

Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone

Gene Expression Profiling in Pediatric Appendicitis

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