Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

Abstract

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-α, IL-6 and IL-1β. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.

CXCR4 as a novel target in immunology: moving away from typical antagonists

“…A set of small molecules including endogenous monoamines (histamine, dopamine, serotonin) and the histamine synthetic analogue clobenpropit (CB) [ 24 , 37 ] as well as the CXCR4 specific isothiourea secondary amine IT1t [ 25 ] downmodulate inflammation in different settings (see Figure 1 A–E for compound structures). IT1t was, until now, most often reported as an antagonist of CXCR4 resulting in potent and dose-dependent inhibition of the CXCL12/CXCR4 interaction [ 38 ].…”

“…Furthermore, ex vivo peripheral blood mononuclear cells from lupus patients show reduced levels of IFNα, TNFα, IL-6, TRAIL and STAT1/3 phosphorylation after pre-incubation with IT1t [ 25 ]. Recently, the immunomodulatory effect of CB was confirmed on whole blood from COVID-19 patients as TNFα, IL-1β, IL-6 and IL-10 expression levels were also inhibited [ 37 ]. These studies using patient samples demonstrate the direct relevance of the compounds in a disease setting and their potential as therapeutic application.…”