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James J. Lee, PhD, Cheryl A. Protheroe, BA, Huijun Luo, PhD, Sergei I

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Presentation on theme: "James J. Lee, PhD, Cheryl A. Protheroe, BA, Huijun Luo, PhD, Sergei I"— Presentation transcript:

1 Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice 
James J. Lee, PhD, Cheryl A. Protheroe, BA, Huijun Luo, PhD, Sergei I. Ochkur, PhD, Gregory D. Scott, BS, Katie R. Zellner, MS, Randall J. Raish, MS, Mark V. Dahl, MD, Miriam L. Vega, MD, MPH, Olivia Conley, Rachel M. Condjella, PhD, Jake A. Kloeber, Joseph L. Neely, Yash S. Patel, Patty Maizer, MS, Andrew Mazzolini, MA, Allison D. Fryer, PhD, Noah W. Jacoby, David B. Jacoby, MD, Nancy A. Lee, PhD  Journal of Allergy and Clinical Immunology  Volume 135, Issue 2, Pages e1 (February 2015) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Toxicant contact exposure protocols to either DNFB or TMA. Experimental and control mice were sensitized by exposure to DNFB (A) or TMA (B) and subsequently toxicant-challenged (left ear) in the time frames described, with the contralateral right ear of each mouse challenged using vehicle alone (DNFB, olive oil:acetone [3:1] or TMA, olive oil:acetone [4:1]) to provide negative controls for exposure. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 The toxicant-contact skin reactions that follow exposure to TMA, but not DNFB, elicit a robust differential recruitment and/or accumulation of eosinophils. Infiltrating eosinophils in ear biopsies following exposure to TMA or DNFB were identified by immunohistochemistry using a rat anti-mouse major basic protein monoclonal antibody; negative control biopsies were derived from contralateral ears exposed to vehicle alone (DNFB, olive oil:acetone [3:1] or TMA, olive oil:acetone [4:1]). Scale bar = 100 μm. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Ear tissue biopsies demonstrate that eosinophil-mediated activities contribute to TMA-induced inflammatory and remodeling responses. A, Hematoxylin-eosin stained sections of ear tissue biopsies from wild-type and eosinophil-deficient PHIL mice exposed to TMA (negative controls are contralateral ears exposed to vehicle alone (olive oil:acetone [4:1]). Scale bar = 50 μm. B, Representative picrosirius-red-stained ear sections from wild-type and age-matched (12 weeks postpartum) eosinophil-deficient PHIL mice (visualized under polarized light). E, Epidermis; M, muscularis; CA, cartilage. Scale bar = 100 μm. C, Under polarized light, the sub-epidermal interstitial area within each entire ear biopsy from 5 to 9 mice per group was evaluated at a magnification of 200×, evaluating the area underlying ≥0.7 mm linear length of epidermis. The extent and intensity of picrosirius red staining was quantified as the sum total (∑) of pixel values (pixel number × average pixel intensity within the region surrounding the basement membrane of epidermis normalized to the total linear length of epidermis evaluated). n.s., Not significant, *P < .05. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 The remodeling events linked with eosinophils infiltrating the skin contribute to the increased ear thickness that occurs following exposure to TMA. Ear thickness (mm) of previously sensitized wild type (clear circle) vs eosinophil-deficient PHIL (black circle) mice challenged with TMA was measured on protocol day 15 using a micrometer as a surrogate maker for tissue edema; contralateral ears exposed to vehicle alone (olive oil:acetone [4:1]) were used as negative controls. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 TMA-induced skin inflammatory responses lead not only to eosinophil accumulation but also to eosinophil degranulation and the release of secondary granule components within the interstitium underlying the epidermis. EPX-mAb-based immunohistochemistry of ear biopsies (n = 5/cohort) demonstrated that a spectrum of eosinophil infiltration and degranulation levels occur in TMA-challenged wild-type mice. A, Representative moderate (160×, 1.8 mm2 field-of-view) power photomicrographs were used to identify the maximum foci of eosinophil infiltration in each biopsy (Table I). Scale bar = 100μm. B, Representative photomicrographs (400× hpf [0.29 mm2 field-of-view]) of each level of degranulation (Table I) as determined by EPX-mAb-based immunohistochemistry (magenta staining cells and extracellular matrix regions). Scale bar = 100 μm. C, The EAI algorithm, representing both eosinophil tissue infiltration and eosinophil degranulation (Table I), was used to quantify eosinophil-mediated activities in the skin of TMA-challenged wild-type vs PHIL mice; negative controls are vehicle-alone treated ears (olive oil:acetone [4:1]). *P < .05. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 TMA-induced inflammation elicits an eosinophil-dependent increase of sensory nerve innervation of the skin. A, Representative confocal immunofluorescence images of wild-type and eosinophil-deficient PHIL mice following challenge with TMA. Control exposures were vehicle-alone (acetone:olive oil [4:1], identifying all dermal [PGP 9.5; green]) and sensory dermal (substance P [red]) nerves. Scale bar = 100 μm. B, The quantification of the TMA-mediated increase in substance P-expressing nerve density (relative to vehicle-alone treated contralateral ears) demonstrated that unlike total innervation, which did not change between wild-type and PHIL ears treated with vehicle-alone (acetone:olive oil [4:1]), the density of substance P-expressing nerves increased (relative to contralateral ear treated with vehicle alone) in TMA-treated wild-type ears (n = 4), with ears from TMA-treated eosinophil-deficient PHIL mice displaying no increase in these nerves (n = 3). *P < .05. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 The induced itching occurring in response to TMA-mediated inflammation is an eosinophil-dependent phenomenon. TMA-mediated itching events were assessed from time-lapsed videography following the last TMA exposure (ie, the night between protocol days 14 and 15). Quantification of itching events in wild-type (clear circle) vs eosinophil-deficient PHIL (black circle) mice was assessed relative to the contralateral control ear from the same mouse by 3 intra/inter-observer blinded investigators (n = 7-8 mice/group). These data showed that the induced itching associated with TMA-mediated inflammation was significantly lower in the absence of eosinophils (PHIL) compared with itching events occurring in wild-type mice. *P < .05. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 The toxicant-contact skin reactions occurring in eosinophil-deficient PHIL mice (relative to wild type) following exposure to TMA are accompanied by lower numbers of resident mast cells and variable levels of mast cell degranulation. Infiltrating mast cells and the extent of mast cell degranulation in ear biopsies following exposure to TMA were assessed by immunohistochemistry using an anti-mast cell tryptase monoclonal antibody; negative control biopsies were derived from contralateral ears exposed to vehicle alone (olive oil:acetone [4:1]). These data showed that TMA-treated wild-type mice uniformly displayed significant inflammatory changes that included increases in mast cell numbers and extensive degranulation. In contrast, TMA-treatment of PHIL mice elicited only nominal increases in mast cell numbers while inducing variable levels of mast cell degranulation. Scale bar = 1 mm. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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