GPR18 Controls Reconstitution of Mouse Small Intestine Intraepithelial Lymphocytes following Bone Marrow Transplantation

Abstract

Specific G protein coupled receptors (GPRs) regulate the proper positioning, function, and development of immune lineage subsets. Here, we demonstrate that GPR18 regulates the reconstitution of intraepithelial lymphocytes (IELs) of the small intestine following bone marrow transplantation. Through analysis of transcriptional microarray data, we find that GPR18 is highly expressed in IELs, lymphoid progenitors, and mature follicular B cells. To establish the physiological role of this largely uncharacterized GPR, we generated Gpr18-/- mice. Despite high levels of GPR18 expression in specific hematopoietic progenitors, Gpr18-/- mice have no defects in lymphopoiesis or myelopoiesis. Moreover, antibody responses following immunization with hapten-protein conjugates or infection with West Nile virus are normal in Gpr18-/- mice. Steady-state numbers of IELs are also normal in Gpr18-/- mice. However, competitive bone marrow reconstitution experiments demonstrate that GPR18 is cell-intrinsically required for the optimal restoration of small intestine TCRγδ+ and TCRαβ+ CD8αα+ IELs. In contrast, GPR18 is dispensable for the reconstitution of large intestine IELs. Moreover, Gpr18-/- bone marrow reconstitutes small intestine IELs similarly to controls in athymic recipients. Gpr18-/- chimeras show no changes in susceptibility to intestinal insults such as Citrobacter rodentium infections or graft versus host disease. These data reveal highly specific requirements for GPR18 in the development and reconstitution of thymus-derived intestinal IEL subsets in the steady-state and after bone marrow transplantation.

Shufeng Jiedu Capsules Alleviate Lipopolysaccharide-Induced Acute Lung Inflammatory Injury via Activation of GPR18 by Verbenalin

“…On the other hand, verbenalin showed inhibitory effects on inflammation responses in GPR18-KO mice, but this effect was significantly weaker than that in WT mice, indicating the role of GPR18 in the antiinflammatory effects or verbenalin. Our results are consistent with a previous study, which showed that GPR18 regulates the reconstitution of mouse small intestine intraepithelial lymphocytes [35]. Other reported functions of GPR18 include its modulation of myocardial function, blood pressure, and intraocular pressure [36,37].…”

Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors. Relevance in neurodegenerative diseases

“…GPR18 is widely expressed in different tissues and cell types. GPR18 expression was first described in spleen, thymus, bone marrow, leucocytes and macrophages (Gantz et al, 1997;Vassilatis et al, 2003;Kohno et al, 2006;Regard et al, 2008;Takenouchi et al, 2012;Becker et al, 2015). However, receptor is also expressed in the central nervous system (CNS) (Vassilatis et al, 2003;Regard et al, 2008;Penumarti and Abdel-Rahman, 2014), in particular in microglia (Walter et al, 2003), in testis, ovary, lungs, intestine (Gantz et al, 1997;Vassilatis et al, 2003), eye (Caldwell et al, 2013) and cancerous cells (McHugh et al, 2010(McHugh et al, , 2012Qin et al, 2011).…”

“…In the periphery, regulating the immune system, GPR18 is involved in resolving inflammation (Burstein et al, 2011), regulating macrophage apoptosis (Takenouchi et al, 2012) and controlling the fate of intestine intraepithelial lymphocytes following bone marrow transplantation (Becker et al, 2015). It is also involved in regulating hemodynamic responses (Parmar and Ho, 2010;Penumarti and Abdel-Rahman, 2014;Al Suleimani and Al Mahruqi, 2017;Matouk et al, 2017), cell migration (Walter et al, 2003;McHugh et al, 2010) and intraocular pressure (Miller et al, 2016).…”

G protein coupled receptor 18: A potential role for endocannabinoid signaling in metabolic dysfunction

“…Of importance, the latest study by Becker et al. confirms that GPR18 controls reconstitution of mouse small intestine intraepithelial lymphocytes following bone marrow transplantation and suggests that manipulation of GPR18 signals could be used to modulate inflammatory disorders . Therefore, it is possible to suggest that GPR18 may play an important immunoregulatory role in the pathophysiology of inflammation associated with obesity and related metabolic disorders (Fig.…”