RNase L represses hair follicle regeneration through altered innate immune signaling
Charles S. Kirby, Nasif Islam, Eric Wier, Martin P. Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S. Lee, Andrew M. Overmiller, Yingchao Xue, Sashank Reddy, Nathan K. Archer, Lloyd S. Miller, Jianshi Yu, Weiliang Huang, Jace W. Jones, Sooah Kim, Maureen A. Kane, Robert H. Silverman, Luis A. Garza
Charles S. Kirby, Nasif Islam, Eric Wier, Martin P. Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S. Lee, Andrew M. Overmiller, Yingchao Xue, Sashank Reddy, Nathan K. Archer, Lloyd S. Miller, Jianshi Yu, Weiliang Huang, Jace W. Jones, Sooah Kim, Maureen A. Kane, Robert H. Silverman, Luis A. Garza
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Research Article Dermatology Inflammation

RNase L represses hair follicle regeneration through altered innate immune signaling

Abstract

Mammalian injury responses are predominantly characterized by fibrosis and scarring rather than functional regeneration. This limited regenerative capacity in mammals could reflect a loss of proregeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we screened transcripts in human participants following laser rejuvenation treatment and compared them with mice with enhanced wound-induced hair neogenesis (WIHN), a rare example of mammalian organogenesis. We found that Rnasel–/– mice exhibit an increased regenerative capacity, with elevated WIHN through enhanced IL-36α. Consistent with RNase L’s known role to stimulate caspase-1, we found that pharmacologic inhibition of caspases promoted regeneration in an IL-36–dependent manner in multiple epithelial tissues. We identified a negative feedback loop, where RNase L–activated caspase-1 restrains the proregenerative dsRNA-TLR3 signaling cascade through the cleavage of toll-like adaptor protein TRIF. Through integrated single-cell RNA-seq and spatial transcriptomic profiling, we confirmed OAS & IL-36 genes to be highly expressed at the site of wounding and elevated in Rnasel–/– mouse wounds. This work suggests that RNase L functions as a regeneration repressor gene, in a functional trade off that tempers immune hyperactivation during viral infection at the cost of inhibiting regeneration.

Authors

Charles S. Kirby, Nasif Islam, Eric Wier, Martin P. Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S. Lee, Andrew M. Overmiller, Yingchao Xue, Sashank Reddy, Nathan K. Archer, Lloyd S. Miller, Jianshi Yu, Weiliang Huang, Jace W. Jones, Sooah Kim, Maureen A. Kane, Robert H. Silverman, Luis A. Garza

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Figure 2

RNase L–loss enhances hair follicle regeneration.

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RNase L–loss enhances hair follicle regeneration. (A) Rnasel–/– mice exh...
(A) Rnasel–/– mice exhibit increased WIHN with an intact superincrease in the presence of poly (I:C) (confocal scanning laser microscopy [CSLM] and Alkaline Phosphatase [AP]staining, images; n = 12 WT, 13 WT+PIC and 12 Rnasel–/–, 13 Rnasel–/–+PIC, 2-way ANOVA, P < 0.0001). In each image, the dash red box indicates the area of hair follicle regeneration. (B) Rnasel–/– mice display normal wound closure speed (n = 20 WT mice and 17 Rnasel–/– mice). (C) Transepidermal water loss (TEWL) was measured in the center and periphery of healed skin at scab detachment day (Would Day 10 [WD10]) for both WT and Rnasel–/– mice. Rnasel–/– mice exhibit dramatically lower TEWL measurements, consistent with a postwounding improved barrier compared with WT mice (n=3, 2-tailed unpaired t test, P < 0.005, P = 0.001). (D) Rnasel–/– mice have greater morphogenesis marker gene expression of Tlr3 (n = 3, P < 0.01), Il6 (n = 3, P < 0.0001), Wnt7b (n = 3, P < 0.01), and Edar (n = 3, 2-tailed unpaired t test, P < 0.01) on day of reepithelialization as measured by qRT-PCR. (E) Unwounded skin of Rnasel–/– mice shows increased protein expression of stem cell markers KRT5 (green) and KRT15 (red) and morphogenesis marker WNT7B (green) shown by immunofluorescence (original magnification, × 20).