Impact of histamine H4 receptor deficiency on the modulation of T cells in a murine breast cancer model.

BACKGROUND: The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. METHODS: We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. RESULTS: The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. CONCLUSIONS: H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis.

Activation of ERK/CREB pathway in noradrenergic neurons contributes to hypernociceptive phenotype in H4 receptor knockout mice after nerve injury.

G-protein coupled receptor H4 (H4R) is a histamine receptor subtype that is involved in a condition of pathological chronic pain, but its pathophysiological function is unknown. Here, we investigate the role of H4R in a model of traumatic nerve injury. H4R knockout (H4R-/-) mice exposed to spared nerve injury (SNI) developed a more prominent mechanical and thermal hypersensitivity than wild type mice. Western blotting and immunofluorescence were used to characterize the cellular mechanisms. Nerve injury increased phosphorylated pERK MAPK expression in the spinal cord that was further promoted in H4R-/- genotype. Additionally, the increase in the phosphorylated cAMP response element-binding protein (CREB) was significantly enhanced in neuropathic H4R-/- mice. In the same way, after SNI a remarkable increase of dopamine beta-hydroxylase (DßH) immunoreactive neurons was detected in spinal cord of H4R-/- mice. The number of injured DRG neurons after SNI of H4R-/- mice, identified by activating transcription factor 3 (ATF3) staining was comparable to that of wild type littermates. Similarly the density of intraepidermal nerve fibres in plantar skin after SNI was reduced with the same degree in H4R-/- mice and with wild type mice. We conclude that the phenotype of H4R-/- mice leads to increased neuropathic pain hypersensitivity promoting an overactivation of spinal ERK-CREB pathway in DßH expressing neurons without modifying the innervation of the hind paw skin and integrity of the primary sensory neurons. In summary, our results provide H4R as a potential new target for the clinical management of chronic neuropathic pain conditions.