Fig 2: Immunohistochemical analysis of inflammatory lesions observed in pancreatic tissues from PRSS1 transgenic mice. Immunohistochemical analysis of inflammatory infiltrates in 8.5-month-old heterozygous animals from each transgenic strain and age-matched WT control, as indicated, using cell-type-specific marker antibodies for: (a) T cells (CD3), (b) B cells (CD20), (c) macrophages (F4/80) and (d) activated pancreatic stellate cells (PSCs), identified by staining for alpha-smooth muscle actin (α-SMA). Insets represent magnified areas of the photomicrographs (original magnification × 200). (e) WB analysis of pancreatic tissue isolated from littermates derived from an intercross of PRSS1 heterozygous animals using antibodies specific for α-SMA, HA and β actin as indicated. Please note that the same blot was probed for SPINK3, shown in Supplementary Figure 3. P=animal with pancreatitis observed by histological analysis; N, histologically normal animal; wt, wild-type animal of the same genetic background; M, molecular weight marker (kDa)

Fig 3: PD-1 deficiency only slightly affects CD4+ T cell polarization towards the Th1 lineage.a) Representative FACS dot plots and quantification of frequencies of IL-17A and IFN?-expressing cells in pre-gated CD45+CD3+TCRß+ CD4+ T cells in blood (a), spleen (b) and peripheral LN (c) of Ldlr- /- or Ldlr- /- Pd1- /- mice after 9 weeks of high fat diet feeding (n = 5/group, representative of 2 independent experiments). **p<0.01.

Fig 4: IL-6 signaling deficiency reduces alopecia and radiodermatitis in irradiated mice ARelative expression and co-localization of IL6 mRNA and IL-6 Signaling Scoring in integrated skin cells by blended UMAPs.BQuantification by real-time qPCR analysis of Il6 mRNA in the skin of naïve and irradiated (15 Gy) WT mice at indicated times, (n = 3–6).CQuantification of ventral hair loss area 21 days post-IR (15 Gy) in WT and IL-6-/- mice, (n = 11).DPhotographic images showing hair loss (area demarked by yellow dashed line) 21 days post-IR (15 Gy) in wild type (WT) and IL-6-/- mice.EHistochemical (H&E) and immunostaining (red) showing skin morphology, and T-cell (CD3+) and neutrophil (Ly6b+) infiltration in WT or IL-6-/- mice before (naïve), and 14 days (H&E, Ly6b+), or 21 days (CD3+) post-IR. Infiltrating CD3+ T cells (yellow arrows) within degenerating hair follicles (HF; dashed lines) are indicated. Scale bars, 100 µm.FQuantification of epidermal thickness at 14 days post-IR (n = 5–8).GKinetics of neutrophil (Ly6b+; n = 3–9) and T-cell (CD3+; n = 3) infiltration.HQuantification by real-time qPCR analysis of Tnfa and Ccl3 mRNAs in whole skin of WT and IL-6-/- mice at indicated times post-IR (15 Gy), (n = 5–7). Data information: Data represent mean ± SD (B, C, F, H) or mean ± SEM (G). *P < 0.05, **P < 0.01, **P < 0.01, ****P < 0.001 by one-way ANOVA with Dunnett's multiple comparison test (B), two-tailed Mann–Whitney test (C, F, H), or two-way ANOVA with Bonferroni's post hoc multiple comparisons test (G); five independent experiments (See also Fig EV3 and Appendix Figs S7 and S9). Source data are available online for this figure.

Fig 5: Blockade of STAT3 activation reduces IRIAD AWestern blot analysis shows phosphorylated STAT3 (p-Stat3), Erk1 and Erk2 (p-Erk1/2), and ß-Actin in the skin of WT, IL-6-/-, and IL-1R-/- mice at indicated times (days) post-IR (15 Gy).BHistochemical (H&E) and immunostaining (red) staining of T cells (CD3+), neutrophils (Ly6b+), and phosphorylated Stat3 (p-Stat3; red nuclear staining, black arrows) in skin thin sections prepared at 14 days post-IR from mice treated by daily topical application of aquosum (control), ruxolitinib, or tofacitinib following irradiation (15 Gy). Scale bar, 100 µm. (CD3 and Ly6b immunostaining images from Tofacitinib-treated mice represent separate analyses performed on serial thin sections.)CQuantification of epidermal thickness, T cells (CD3+) and neutrophils (Ly6b+), and p-STAT3+ cells in (B), (n = 4).DPhotographic images showing hair loss in mice at 14 days post-IR (15 Gy) following treatment by daily topical application of aquosum (carrier control) or JAK inhibitors, ruxolitinib, or tofacitinib. Chest and neck hairs of mice in all groups were clipped prior to irradiation to enhance drug absorption.EQuantification of the area of ventral hair loss (in pixels) in mice in (D), (n = 4). Data information: Data represent mean ± SD. *P < 0.05, **P < 0.01, by two-tailed Student's t-test; two independent experiments (See also Appendix Fig S8). Source data are available online for this figure.