The histamine H4 receptor modulates the differentiation process of human monocyte-derived M1 macrophages and the release of CCL4/MIP-1β from fully differentiated M1 macrophages
- 229 Downloads
Histamine is an important mediator of biological functions and present in high amounts in inflammatory skin lesions which are characterised by a marked infiltration of myeloid derived cell populations. The aim of the study was to investigate the expression and function of histamine receptors, with a focus on the histamine H4 receptor (H4R) in detail during the differentiation process from monocytes to macrophages and on fully differentiated M1 macrophages.
Quantitative PCR, ELISA technique, and flow cytometry were applied to analyze expression levels of histamine receptors, of CXCL10, CCL4, CCL3, or IL-23 and of the macrophage differentiation marker CD68, respectively.
We demonstrated that monocytes and fully differentiated M1 macrophages express H1R-, H2R-, and H4R mRNA which were differentially regulated during the differentiation process and in IFN-Ƴ and LPS classically activated M1 macrophages. The H3R mRNA was not expressed. During in vitro differentiation from monocytes to macrophages, the H4R agonist ST-1006 modified the M1 phenotype by up-regulating the macrophage differentiation marker CD68, by down-regulating the production of CXCL10, and by changing the morphology. In fully differentiated M1 macrophages, histamine or ST-1006 decreased the IFN-Ƴ- and LPS-induced CCL4 mRNA expression and protein production, whereas CCL3 or IL-23 production was not regulated via H4R.
We describe novel immunomodulatory functions of the H4R during the differentiation process of human monocyte-derived macrophages and in fully differentiated M1 macrophages. The down-regulation of Th1-related chemokines during the differentiation process or in classically activated macrophages via H4R may contribute to decreased migration of immune cells to the site of inflammation. This may have implications for the treatment of allergic diseases with H4R ligands regulating the dysbalance of Th2/Th1 polarizations in these disorders.
KeywordsM1 macrophages Histamine H4 receptor Cell shape
Histamine H4 receptor
The authors would like to thank Brigitta Koether and Kira Herwig for excellent technical assistance.
SM is the primary author and analyzed the histamine receptor expression on human macrophages, conducted data collection, analysis, interpretation of the data and writing the first draft of the manuscript. LR performed most of the experiments, generating and stimulating the macrophages and performing ELISA and qPCR. HS provided the H4R-agonist ST-1006 and made contributions to the conception, design and interpretation of the data. RG and TW made significant and substantial contributions to the conception, design and interpretation of the data. All authors reviewed, revised, and approved the manuscript for publication.
This study was supported by Grants from the Deutsche Forschungsgemeinschaft DFG: Gu434/6-1. Funding for this research was provided by Janssen Research & Development, LLC.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to declare.
- 1.Hume DA, Summers KM, Rehli M. Transcriptional regulation and macrophage differentiation. Microbiol Spectr. 2016;MCHD-0024-2015.Google Scholar
- 35.Kutukculer N, Azarsiz E, Aksu G, Karaca NE. CD4 + CD25 + Foxp3 + T regulatory cells, Th1 (CCR5, IL-2, IFN-γ) and Th2 (CCR4, IL-4, Il-13) type chemokine receptors and intracellular cytokines in children with common variableimmunodeficiency. Int J Immunopathol Pharmacol. 2016;29:241–51.CrossRefPubMedGoogle Scholar
- 38.Werfel T, Lynch V, Asher A, Tsianakas A, Gupta B, Sarmiento R, et al. Allergy. 2016;71(Suppl.102):95.Google Scholar