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G protein coupled receptors in inflammation - from kinin to chemokine
G protein coupled receptors in inflammation - from kinin to chemokine
At the core of all noncommunicable diseases (NCDs) such as cancer and cardiovascular disease, is inflammation, a highly complexed process tightly orchestrating the action of multiple inflammatory molecules. Among the receptors expressed by the hematopoietic and non-hematopoietic cells, G protein-coupled receptors (GPCRs) play a key role in inflammation as they are activated by different inflammatory molecules such as amines, peptides, eicosanoids, and chemokines. The first studies summarized here unveiled a novel pathway of inflammation involving the interconnection between two GPCRs, namely the kinin B1 receptor (B1R) and the CXC chemokine receptor 2 (CXCR2). The inflammatory cytokine, IL-1β, and proatherogenic factors were identified to induce the production of the CXCL5 chemokine in endothelial cells through a B1R-dependent mechanism in acute conditions. In turn, the release of CXCL5 at the surface of endothelial cells resulted in the recruitment of CXCR2+ neutrophils into the inflamed tissue. The next study highlighted an unexpected role for the CXCL5 chemokine in chronic inflammatory disease. While CXCL5 was highly expressed by endothelial cells, its induction was protective in atherosclerotic conditions. CXCL5 was found to activate macrophages, increase the expression of ACBA1, a transporter that mediates cholesterol efflux, and consequently regulate foam cell formation. The last studies focused on a particular class of chemokine receptors, so-called atypical chemokine receptors (ACKRs) and more specifically on ACKR1, which is highly expressed by erythroblasts in the bone marrow. ACKR1 was identified as a regulator of homeostasis of haematopoietic stem and progenitor cells (HSPCs) and to control downstream hematopoiesis. Notably, erythroblasts were shown to directly interact with HSPCs in an ACKR1-dependent manner. In the absence of ACKR1, steady-state haematopoiesis was altered, bone marrow HSPCs localized remotely from erythroblasts and gave rise to phenotypically distinct neutrophils. Altogether, the work presented here provides additional evidence that the chemokine system via its action on the classical but also the atypical chemokine receptors, plays a crucial role on hematopoietic cells and in inflammation. Moreover, this work highlights the complexity of chemokine targeting in NCDs, as the same chemokine may have distinct biological effects in different inflammatory diseases. Further research is therefore required to fully apprehend the contribution of GPCRs and especially ACKRs in NCDs, to elucidate pathological mechanisms, and to ultimately develop new drug therapies targeting these receptors.
Inflammation, Chemokine, Kinin, GPCR
Duchêne, Johan
2023
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Duchêne, Johan (2023): G protein coupled receptors in inflammation - from kinin to chemokine. Habilitationsschrift, LMU München: Faculty of Medicine
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Abstract

At the core of all noncommunicable diseases (NCDs) such as cancer and cardiovascular disease, is inflammation, a highly complexed process tightly orchestrating the action of multiple inflammatory molecules. Among the receptors expressed by the hematopoietic and non-hematopoietic cells, G protein-coupled receptors (GPCRs) play a key role in inflammation as they are activated by different inflammatory molecules such as amines, peptides, eicosanoids, and chemokines. The first studies summarized here unveiled a novel pathway of inflammation involving the interconnection between two GPCRs, namely the kinin B1 receptor (B1R) and the CXC chemokine receptor 2 (CXCR2). The inflammatory cytokine, IL-1β, and proatherogenic factors were identified to induce the production of the CXCL5 chemokine in endothelial cells through a B1R-dependent mechanism in acute conditions. In turn, the release of CXCL5 at the surface of endothelial cells resulted in the recruitment of CXCR2+ neutrophils into the inflamed tissue. The next study highlighted an unexpected role for the CXCL5 chemokine in chronic inflammatory disease. While CXCL5 was highly expressed by endothelial cells, its induction was protective in atherosclerotic conditions. CXCL5 was found to activate macrophages, increase the expression of ACBA1, a transporter that mediates cholesterol efflux, and consequently regulate foam cell formation. The last studies focused on a particular class of chemokine receptors, so-called atypical chemokine receptors (ACKRs) and more specifically on ACKR1, which is highly expressed by erythroblasts in the bone marrow. ACKR1 was identified as a regulator of homeostasis of haematopoietic stem and progenitor cells (HSPCs) and to control downstream hematopoiesis. Notably, erythroblasts were shown to directly interact with HSPCs in an ACKR1-dependent manner. In the absence of ACKR1, steady-state haematopoiesis was altered, bone marrow HSPCs localized remotely from erythroblasts and gave rise to phenotypically distinct neutrophils. Altogether, the work presented here provides additional evidence that the chemokine system via its action on the classical but also the atypical chemokine receptors, plays a crucial role on hematopoietic cells and in inflammation. Moreover, this work highlights the complexity of chemokine targeting in NCDs, as the same chemokine may have distinct biological effects in different inflammatory diseases. Further research is therefore required to fully apprehend the contribution of GPCRs and especially ACKRs in NCDs, to elucidate pathological mechanisms, and to ultimately develop new drug therapies targeting these receptors.