How does the skin heal wounds?

Wounds are an unavoidable part of our life. Some heal fast, some take time, some leave scars behind. An organ in the human body with the inherent ability to heal itself is the skin. How does the skin do this

Sustained Secretion of the Antimicrobial Peptide S100A7 Is Dependent on the Downregulation of Caspase-8

Summary: Antimicrobial peptides (AMPs) are the body's natural innate immune defense against a spectrum of pathogens and can also modulate cell proliferation, chemotaxis, angiogenesis, wound healing, and immune cell activity. Harnessing these diverse functions for prophylactic use is contingent upon understanding the regulatory mechanisms governing their unconventional secretion from cells. Analysis of the secretion of S100A7 (Psoriasin), an abundant AMP stored in differentiated keratinocytes of the skin, has revealed an unexpected biphasic secretory response to bacterial exposure. The core components regulating S100A7 secretion are NFκB/p38MAPK, caspase-1, and interleukin (IL)-1α. The initial activation of this core machinery is mediated by Toll-like receptor signaling, whereas the chronic response is mediated by Caspase-8 downregulation. Interestingly, there is a concomitant downregulation of Caspase-8 in inflammatory skin diseases wherein S100A7 is constitutively released. These results highlight the potential of targeting these components to control the release of AMPs from the skin in both homeostatic and disease conditions. : The global explosion of antibiotic-resistant microorganisms has spurred interest in alternative strategies to combat these "superbugs." Antimicrobial peptides (AMPs) have emerged as a promising solution. Bhatt et al. show downregulation of epidermal caspase-8 can mediate sustained release of AMPs from the skin and provide an effective defense against infection. keywords: caspase, antimicrobial peptides, skin, TLR, IL-1, NFkB, psoriasis, antibiotic resistanc

Kinetics of caspase-8 promoter methylation and expression.

(A) Levels of caspase-8 mRNA at different time points post-scratch wound (fold change) (n = 4). (B) In vitro ISH of caspase-8 mRNA showing its levels at scratch margins over time [scale = 10 μm]. (C) In vivo ISH of caspase-8 mRNA showing its levels at wound proximal and distal regions over time (dotted line represents basement membrane, Epi = Epidermis, Der = Dermis) [scale = 20 μm]. (D) Bisulphite sequencing of caspase-8 promoter proximal region (265 bp) shows methylation status of 10 individual CpG sites (columns) from 10 cloned PCR products (rows) at various time points post-scratch wound. Percentage value denotes the percent methylation for each group of CpG sites over time (refer S1D Fig for the sequenced region and primer sites, n = 5 with 2 technical replicates). (Data are shown as mean ± SEM, P-values were calculated using 1-way ANOVA with Dunnett’s test and 2-tailed t test (A), *** P ≤ 0.001, ns = P > 0.05). Data underlying the graphs can be found in Fig 1A of S1 Raw Data.</p

S2 Fig -

(A) Representative image of unwounded/wound-distal skin section stained with DNMT3a, DAPI, and K5. (B’) A model showing the quantification method of DAPI and DNMT3a stain intensities over the line of interest (1, 2) from proliferating and differentiated keratinocytes, followed by (B”) the plots of intensity values (gray unit) (calculated intensities from 4 biological replicates). Staining of in vitro proliferating and differentiated keratinocytes with (C), DNMT3a/DAPI and (D), DNMT3b/DAPI. (E) DNMT3b/DAPI staining of scratch wounded in vitro differentiated keratinocytes. (F) DNMT3a western blot analysis from control and scratch wounded keratinocytes at 8-hour time point (G), DNMT3a, DAPI, and K5 staining of a completely healed mouse skin section [scale = 20 μm]. Data underlying the graphs can be found in S2B Fig of S1 Raw Data. (TIF)</p

NGS read counts.

NGS read counts.</p