CCR1 antagonist J-113863 corrects the imbalance of pro- and anti-inflammatory cytokines in a SJL/J mouse model of relapsing-remitting multiple sclerosis

Article

Author: Ahmad, Sheikh F ; Albekairi, Norah A ; Alanazi, Mohammed M ; Attia, Sabry M ; Alhamed, Abdullah S ; Bakheet, Saleh A ; Shahid, Mudassar ; Ansari, Mushtaq A ; Rehman, Muneeb U ; Ibrahim, Khalid E ; Nadeem, Ahmed

Multiple sclerosis (MS), an immune-mediated and neurodegenerative disorder of the central nervous system (CNS), is characterized by infiltrating myelin-reactive T lymphocytes and demyelinating lesions. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model used to study MS. To explore the impact of chemokine receptor CCR1 blockade in EAE and the underlying mechanisms, we used CCR1 antagonist J-113863 in PLP_139-151-induced EAE in SJL/J mice. Following EAE induction, mice were treated with J-113863 (10 mg/kg) daily from day 14 until day 25. We investigated the effect of J-113863 on expression levels of GM-CSF, IL-6, IL-10, IL-27 in CD4⁺ spleen cells, using flow cytometry. We also analyzed the effect of J-113863 on GM-CSF, IL-6, IL-10, IL-27 mRNA and protein expression levels using RT-PCR and Western blot analysis in brain tissues. J-113863 treatment decreased the populations of CD4⁺GM-CSF⁺ and CD4⁺IL-6⁺ cells and increased CD4⁺IL-27⁺ and CD4⁺IL-10⁺ cells in the spleen. J-113863 had a suppressive effect on the mRNA and protein expression levels of GM-CSF, and IL-6 in the brain tissue. On the other hand, J-113863 treatment increased the mRNA and protein expression of IL-10 and IL-27 in the brain tissue. Our results highlighted J-113863's potential role in suppressing pro-inflammatory expression and up-regulating anti-inflammatory mediators, which could represent a beneficial alternative approach to MS treatment.

01 Apr 2022·Molecular ImmunologyQ3 · MEDICINE

CCR1 antagonist ameliorates experimental autoimmune encephalomyelitis by inhibition of Th9/Th22-related markers in the brain and periphery

Q3 · MEDICINE

Article

Author: Al-Mazroua, Haneen A ; Ansari, Mushtaq A ; Ali, Nemat ; Attia, Sabry M ; Alasmari, Fawaz ; Albekairi, Thamer H ; Algahtani, Mohammad ; Bakheet, Saleh A ; Ahmad, Sheikh F ; Alsaad, Abdulaziz M S ; Nadeem, Ahmed

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. The disease manifestation is associated with the proliferation and activation of lymphocytes and astrocytes, leading to demyelination and neuronal damage. Most of the current therapies are not completely effective, and few target the underlying pathophysiology of MS. T helper 9 (Th9)- and Th22-dominant cells have been proven to play a pathogenic role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The goal of the present study was to investigate the therapeutic efficacy of J-113863, a novel CCR1 chemokine receptor, on PLP_139-151-induced EAE in SJL/J mice. Following induction of EAE, mice were treated with J-113863 (10 mg/kg) or saline intraperitoneally daily from day 14 until day 25, and the clinical score was evaluated. We further investigated the effect of J-113863 on IL-9, IRF4, IL-22, IFN-γ, STAT3, AhR, and IL-17A in CD3⁺, CD4⁺, CCR6⁺, and CCR8⁺ spleen cells using flow cytometry. We also analyzed the effect of J-113863 on IL-9, IRF4, IL-22, IFN-γ, STAT3, AhR, and IL-17A mRNA expression levels. Our results revealed that J-113863 treatment notably attenuated the severity of clinical scores in EAE mice. J-113863 treatment decreased the percentage expression of CD4⁺IL-9⁺, CCR8⁺IL-9⁺, CD4⁺IRF4⁺, CD3⁺IL-22⁺, CCR6⁺IL-22⁺, CD3⁺IFN-γ⁺, CCR6⁺IFN-γ⁺, CD3⁺STAT3⁺, CCR6⁺STAT3⁺, CD4⁺IL-17A⁺, and CCR6⁺IL-17A⁺, and increased the percentage of CD3⁺AhR⁺, and CCR6⁺AhR⁺ cells in the spleen. These results confirmed that J-113863 suppressed Th9/Th22 cells to reduce demyelination in EAE mice, suggesting its potential role as a novel drug candidate for MS treatment.

01 Apr 2020·ImmunologyQ3 · MEDICINE

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

Q3 · MEDICINE

Article

Author: Mika, Joanna ; Makuch, Wioletta ; Ciapała, Katarzyna ; Popiolek‐Barczyk, Katarzyna ; Kwiatkowski, Klaudia ; Piotrowska, Anna ; Pawlik, Katarzyna

SummaryA growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up‐regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA‐1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin‐1β (IL‐1β), IL‐6 and IL‐18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid‐induced analgesia through the modulation of neuroimmune interactions.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Preclinical	JP	Banyu Pharmaceutical Co. Ltd.	-
Rheumatoid Arthritis	Preclinical	JP	Banyu Pharmaceutical Co. Ltd.	-

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