Mast cell protease 4 limits skin pathologies associated with chronic UVB — ASN Events
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Mast cell protease 4 limits skin pathologies associated with chronic UVB (#137)

Houng H Taing 1 2 , Emma J Gordon 3 , Kelly L Betterman 3 , Kwok H Yip 1 , Gunnar Pejler 4 , Stephen J Galli 5 , Angel F Lopez 1 , Natasha L Harvey 3 , Michele A Grimbaldeston 1 2
  1. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  2. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
  3. Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  4. Department of Anatomy, Physiology and Biochemistry, Swedish Univeristy of Agricultural Sciences, Uppsala, Sweden
  5. Department of Pathology, Stanford University School of Medicine, Stanford, USA

Excessive exposure to ultraviolet-B (UVB) radiation (290-320 nm), a component of sunlight, is considered the major etiologic factor in underlying tumourigenesis of the skin, causing detrimental alterations in the patterns of tissue remodeling processes, sustained inflammation and heightened angiogenesis. Accumulation of mast cells (MCs) in the peri-tumoural stroma is typically a hallmark feature; this has given rise to the important question of whether MC function at the peri-lesional interface provides a permissive tumourigenic environment or guards against rapid neoplastic progression.  Recently, we discovered that MCs can negatively regulate inflammatory responses caused by chronic low-dose UVB irradiation of the skin, via a pathway involving Vitamin D3 and MC-derived IL-10. The regime of UVB exposures used for these studies caused UVB-induced skin damage but no skin tumours. Therefore, in the current study we explored whether MCs maintain a protective regulatory ability in response to higher doses and more excessive exposures of UVB that cause tumour progression and aberrant lymphangiogenesis. In addition to MC-derived IL-10, our findings suggest that the preformed and granule stored chymotrypsin-like serine protease mouse mast cell protease 4 (mMCP4), a modulator of the extracellular matrix, provides protection against the progression of in situ squamous cell carcinoma. We demonstrate MC-deficient c-kit mutant KitW/W-v mice engrafted with bone marrow-derived cultured mast cells (BMCMCs) from mMCP4-/- or IL-10-/- mice, yield higher rates of UVB-induced ear ulceration and skin neoplasia than wild-type BMCMC-engrafted KitW/W-v mice. Interestingly, in response to extensive chronic UVB irradiation mMCP4-/- BMCMC->KitW/W-v mice, exhibit enlarged lymphatic vessels in their ears, thereby suggesting a potential role of mMCP4 and its substrates in governing protection against pathological lymph vessel dysfunction at critical stages during skin tumourigenesis. Taken together, our data indicate that MCs contribute towards homeostatic kinetics and processes that regulate and protect against UVB-induced skin carcinogenesis and aberrant lymphangiogenesis.