Biology subjects

Maytin, E. V.

Publications and source records attributed to Maytin, E. V..

5 recordsLinked to original sources

bioRxiv2026

Abnormally low expression of tumor necrosis factor stimulated gene 6 (TSG-6) in obese type 2 diabetic mice contributes to altered inflammation and delayed cutaneous wound healing

Type 2 diabetes mellitus (T2DM) is a chronic disorder associated with obesity and hyperglycemia. T2DM is linked to significant clinical complications such as delayed wound healing and diabetic foot ulcers. Tumor necrosis factor-stimulated gene 6 (TSG-6) is a protein with multiple functions including regulation of cytokine binding to glycosaminoglycans in extracellular matrices and on vascular endothelial walls. Loss of TSG-6 in knockout mice increases skin inflammation and delays wound healing. Here, in both a genetic model (db/db mice) and a dietary model that simulates human T2DM (mice treated with a high-fat diet [HFD] and streptozotocin [STZ]), we observed sustained hyperglycemia and a reproducible delay in wound closure. TSG-6 expression was markedly reduced in diabetic skin in these models, both before injury and post wounding. HFD+STZ diabetic mouse wounds showed elevated levels of pro-inflammatory cytokines (IL-6, TNF-, and MIP-1) and lower levels of the anti-inflammatory cytokine IL-10, relative to normoglycemic mice. Re-introduction of TSG-6 protein into the wounds normalized healing rates, corrected abnormal cytokine expression levels, and increased macrophage accumulation in dermal and adipose compartments. Thus, T2DM is associated with reduced levels of TSG-6 in diabetic skin, which contributes to the pro-inflammatory milieu and the delay in wound closure.

physiology↗

bioRxiv2026

Photodynamic priming with Vitamin D and ALA-based PDT induces intratumoral immune cell recruitment and signaling pathway activation in murine cutaneous squamous cell carcinoma

Photodynamic therapy (PDT) is effective for early epithelial pre-cancers, yet its efficacy in fully-developed cutaneous squamous cell carcinoma (SCC) is limited by immunosuppression in the tumor microenvironment. Vitamin D (VitD) has emerged as a potential neoadjuvant to enhance photodynamic priming in several cancers. Here, we investigated how VitD pretreatment modulates local and systemic immune responses to aminolevulinic acid-based PDT in two immunocompetent murine SCC models (chronic UV-induced SCC, and subcutaneously implanted PDVC57B cells). VitD combined with PDT significantly amplified hallmarks of immunogenic cell death, including calreticulin and HMGB1 expression, and increased recruitment of neutrophils, macrophages, dendritic cells, and CD8 T cells into tumors. Importantly, VitD+PDT produced a higher M1/M2 macrophage ratio, and reduced the number of exhausted (PD-1 expressing) T cells compared to PDT alone. Immune profiling of blood demonstrated enhanced T-cell activation (CD69) and reduced TIM-3 expression on cytotoxic T cells. Transcriptomic analysis revealed pathway enrichment for interferon-/{gamma} signaling and suppression of pro-tumorigenic epithelial-mesenchymal transition and of angiogenesis after VitD+PDT. Collectively, these findings demonstrate that VitD reprograms the immune response to PDT by enhancing cytotoxic immunity while limiting immunosuppressive features. This suggests an immune-priming strategy to consider, possibly alongside immune checkpoint blockade, for treating cutaneous SCC.

cancer biology↗

bioRxiv2022

Inhibition of pyrimidine synthesis in murine skin wounds induces a pyoderma gangrenosum-like neutrophilic dermatosis accompanied by spontaneous gut inflammation

Pyoderma gangrenosum (PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, [~]40% of patients that present with PG have underlying IBD, suggesting shared but unknown pathogenesis mechanisms. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concurrent intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) and pro-inflammatory cellular as well as soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating immature low-density IL-1{beta} primed granulocytes that undergo enhanced NETosis at inflamed tissue sites supported by increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD.

immunology↗

bioRxiv2019

Cutaneous Wounds in Mice Lacking Tumor Necrosis Factor-stimulated Gene-6 Exhibit Delayed Closure and an Abnormal Inflammatory Response

We investigated how loss of tumor necrosis factor-stimulated gene-6 (TSG-6) affects wound closure and skin inflammation. TSG-6 has several known biological functions including enzymatic transfer of heavy chain proteins (HC) from inter--trypsin inhibitor to hyaluronan (HA) to form HC-HA complexes. TSG-6 and HC-HA are constitutively expressed in normal skin and increase post-wounding, but are completely absent in TSG-6 null mice. Wound closure rates are significantly delayed in TSG-6 null mice relative to wildtype mice. Neutrophil recruitment is delayed in early wounds (12 h and Day 1), whereas late wounds (Day 7) show elevated neutrophil accumulation. In addition, the granulation phase is delayed, with persistent blood vessels and reduced dermal collagen at 10 days. The pro-inflammatory cytokine TNF is elevated >3 fold in unwounded TSG-6 null skin, and increases further after wounding (from 12 h to 7 days) before returning to baseline by day 10. Other cytokines examined such as IL-6, IL-10, and MCP-1 showed no consistent differences. Importantly, reintroduction of TSG-6 into TSG-6 null wounds rescues both the delay in wound closure and the aberrant neutrophil phenotype. In summary, our study indicates that TSG-6 plays an important role in regulating wound closure and inflammation during cutaneous wound repair.

physiology↗

bioRxiv2019

CD44 inhibits α-SMA gene expression via a novel G-actin/MRTF mediated pathway that requires TGFβR/p38MAPK activity in murine skin fibroblasts.

Well-regulated differentiation of fibroblasts into myofibroblasts (MF) is critical for skin wound healing. Neoexpression of -smooth muscle actin (-SMA), an established marker for MF differentiation, is driven by TGF{beta} receptor (TGF{beta}R)-mediated signaling. Hyaluronan (HA) and its receptor CD44 may also participate in this process. To further understand this process, primary mouse skin fibroblasts were isolated and treated in vitro with recombinant TGF-{beta}1 (rTGF-{beta}1) to induce -SMA expression. CD44 expression was also increased. Paradoxically, CD44 knockdown by RNA interference (RNAi) led to increased -SMA expression and -SMA-containing stress fibers. Removal of extracellular HA or inhibition of HA synthesis had no effect on -SMA levels, suggesting a dispensable role for HA. Exploration of mechanisms linking CD44 knockdown to -SMA induction, using RNAi and chemical inhibitors, revealed a requirement for non-canonical TGF{beta}R signaling through p38MAPK. Decreased monomeric G-actin but increased filamentous F-actin following CD44 RNAi suggested a possible role for Myocardin-related Transcription Factor (MRTF), a known regulator of -SMA transcription and itself being regulated by G-actin binding. CD44 RNAi promoted nuclear accumulation of MRTF and the binding to its transcriptional cofactor, SRF. MRTF knockdown abrogated the increased -SMA expression caused by CD44 RNAi, suggesting that MRTF is required for CD44-mediated regulation of -SMA. Finally, chemical inhibition of p38MAPK reversed nuclear MRTF accumulation after rTGF-{beta}1 addition or CD44 RNAi, revealing a central requirement for p38MAPK in both cases. We concluded that CD44 regulates -SMA gene expression through cooperation between two intersecting signaling pathways, one mediated by G-actin/MRTF and the other via TGF{beta}R/p38MAPK.

cell biology↗