Mannose reduces hyaluronan and leukocytes in wound granulation tissue and inhibits migration and hyaluronan‐dependent monocyte binding

Abstract

Wound healing is a highly regulated process starting from coagulation and ending in tissue remodeling. The end result varies from perfectly restored tissue, such as in early fetal skin, to scars in adults. The balanced repair process is frequently disturbed by local or systemic factors, like infections and diabetes. A rapid increase of hyaluronan is an inherent feature of wounds and is associated with tissue swelling, epithelial and mesenchymal cell migration and proliferation, and induction of cytokine signaling. Hyaluronan extending from cell surface into structures called cables can trap leukocytes and platelets and change their functions. All these features of hyaluronan modulate inflammation. The present data show that mannose, a recently described inhibitor of hyaluronan synthesis, inhibits dermal fibroblast invasion and prevents the enhanced leukocyte binding to hyaluronan that takes place in cells treated with an inflammatory mediator interleukin-1β. Mannose also reduced hyaluronan in subcutaneous sponge granulation tissue, a model of skin wound, and suppressed its leukocyte recruitment and tissue growth. Mannose thus seems to suppress wounding-induced inflammation in skin by attenuating hyaluronan synthesis.

Interleukin-1β-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats

“…In the present work, we studied whether IL-1␤ exerts a similar effect in keratinocytes and how this CD44 is associated with the formation of the cytokine-induced, extended hyaluronan coats observed previously in these cells (26,33). Our data show that besides slightly increasing CD44 expression, IL-1␤ blocked phosphorylation of CD44 at serine 325 while at the same time it increased CD44 homomeric complexes and binding of CD44 to ezrin.…”

High numbers of macrophages, especially M2‐like (CD163‐positive), correlate with hyaluronan accumulation and poor outcome in breast cancer

“…Several growth factors and cytokines induce HAS expression and increase HA synthesis in inflamed tissues, and the accumulated HA modulates cellular inflammatory responses . It has been shown that inhibition of HA synthesis reduces tissue accumulation of leukocytes, including macrophages . In a murine mammary tumour model with conditional knockout of HAS2 in stromal fibroblasts, macrophage migration into the HA‐deficient tumour stroma was also severely impaired, blocking tumour angiogenesis and lymphangiogenesis .…”

“…16 It has been shown that inhibition of HA synthesis reduces tissue accumulation of leukocytes, including macrophages. 26 In a murine mammary tumour model with conditional knockout of HAS2 in stromal fibroblasts, macrophage migration into the HA-deficient tumour stroma was also severely impaired, blocking tumour angiogenesis and lymphangiogenesis. 22 In agreement with the above results, we found a strong correlation between TAMs, HA, and HASs, suggesting that the increased HAS expression and accumulation of HA also facilitate macrophage infiltration during human breast cancer progression.…”

“…In the Cox multivariate analysis, significant factors correlating with overall survival in the whole patient group were nodal status [P < 0.001, hazard ratio (HR) 26.744], oestrogen receptor status (P = 0.002, HR 9.282), tumour size (P = 0.005, HR 12.914), and the number of CD163-positive cells [P = 0.048, HR 3.924, 95% confidence interval (CI) 1.007-3.698]. Among the HER2-positive patients, significant prognostic factors in the Cox multivariate analysis were nodal status (P = 0.001, HR 16.857), adjuvant trastuzumab treatment (P = 0.001, HR 10.294), and the number of CD163-positive cells (P = 0.016, HR 5.806, 95% CI 1.210-6.389).…”

Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy

“…Mannose at ~20 mM concentration inhibits HA synthesis by causing a reduction in the cellular concentration of UDP- N -acetylhexosamines (i.e., UDP- N -acetyl-D-glucosamine and UDP- N -acety-D-galactosamine). Mannose treatment was shown to inhibit dermal fibroblast invasion and to prevent enhanced leukocyte binding to HA (Jokela et al, 2008, 2013). However, antitumor effects of mannose in the context of HA synthesis inhibition have not yet been investigated.…”