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Review
. 2022 Jan 4:12:731674.
doi: 10.3389/fimmu.2021.731674. eCollection 2021.

Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis

Yuka Okada  1 , Takayoshi Sumioka  1 , Peter S Reinach  2 , Masayasu Miyajima  1 , Shizuya Saika  1
Affiliations
Review

Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis

Yuka Okada et al. Front Immunol. .

Abstract

The maintenance of normal vision is dependent on preserving corneal transparency. For this to occur, this tissue must remain avascular and its stromal architecture needs to be retained. Epithelial transparency is maintained provided the uppermost stratified layers of this tissue are composed of terminally differentiated non-keratinizing cells. In addition, it is essential that the underlying stromal connective tissue remains avascular and scar-free. Keratocytes are the source of fibroblasts that are interspersed within the collagenous framework and the extracellular matrix. In addition, there are sensory nerve fibers whose lineage is possibly either neural crest or mesenchymal. Corneal wound healing studies have been undertaken to delineate the underlying pathogenic responses that result in the development of opacification following chemical injury. An alkali burn is one type of injury that can result in severe and long- lasting losses in ocular transparency. During the subsequent wound healing process, numerous different proinflammatory cytokines and proteolytic enzymes undergo upregulation. Such increases in their expression levels induce maladaptive expression of sustained stromal inflammatory fibrosis, neovascularization, and losses in the smooth optical properties of the corneal outer surface. It is becoming apparent that different transient receptor potential channel (TRP) isoforms are important players in mediating these different events underlying the wound healing process since injury upregulates both their expression levels and functional involvement. In this review, we focus on the involvement of TRPV1, TRPA1 and TRPV4 in mediating some of the responses that underlie the control of anterior ocular tissue homeostasis under normal and pathological conditions. They are expressed on both different cell types throughout this tissue and also on corneal sensory nerve endings. Their roles have been extensively studied as sensors and transducers of environmental stimuli resulting from exposure to intrinsic modulators and extrinsic ligands. These triggers include alteration of the ambient temperature and mechanical stress, etc., that can induce pathophysiological responses underlying losses in tissue transparency activated by wound healing in mice losses in tissue transparency. In this article, experimental findings are reviewed about the role of injury-induced TRP channel activation in mediating inflammatory fibrotic responses during wound healing in mice.

Keywords: TRP; cornea; fibrosis; nurotrophic keratitis; wound healing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Loss of TRPA1 function blunts inflammatory fibrosis responses to corneal injury.(A) Comparison of wound healing progression in wild-type (WT) and TRPA1–null (KO) alkali-burned mouse corneas. At 5, 10, and 20 days after injury, the incidence and degree of opacification and surface irregularity in the healing cornea was more prominent in the WT mice than the TRPA1 KO mice. (B) Hematoxylin and eosin (H&E) histological and immunohistochemical changes in burned corneas at day 10. H&E staining shows that the burned corneas have a larger cell population (presumably inflammatory cells) and the WT cornea appear more disorganized than their KO counterpart. The stromal thickness of the WT corneas is greater than in the KO corneas throughout the entire healing period. Immunohistochemistry findings suggest that the density of the myeloperoxidase (MPO)-labeled polymorphonuclear leukocytes (PMNs) and F4/80-labeled macrophages is larger in the WT cornea than in the KO cornea. During the wound healing process, there appear to be many more αPO)-labeled-positive myofibroblasts in the WT mice than in the TRPA1 KO. Furthermore, the anti-αpositive myofibroblasts in the WT mice than in the TRPA1 KO. Furthermore, the anti-rger in the WT (C) Active TGFβpositive myofibroblasts in the WT mice than in the TRPA1 KO. Furthermore, the anti-rger in (C) Real-time RT-PCR analyses of MPO, F4/80, han in the TRPA1 KO. Furthermore, the anti-rger in the WT c. Activepoint in the TRPA1 KO corneas than those in the WT corneas. Data represent mean ± SEM from five specimens in each condition (bar). *P < 0.05. Reprinted from Okada et al with permission from Lab Invest.
Figure 2
Figure 2
Time dependent healing of an alkali-burned cornea in a bone marrow transplanted (BMT) mouse. (A) A wild-type (WT) mouse is injected with bone marrow (BM) from a WT mouse (WT -to-WT) at 10 and 20 days after alkali burning. The responses are compared with those occurring in a WT mouse that receives instead BM from a TRPA1-null (KO) mouse (KO -to-WT). This manipulation results in greater opacification and neovascularization than in the KO mouse that receives instead BM from a WT mouse (WT –to-KO) group. (B) H&E histology shows increases in cell density in the swollen stroma of a KO-to-WT cornea as compared with a WT-to-KO tissue. Immunohistochemistry indicates that the cornea of a WT-to-KO mouse has less stromal immunoreactivity as compared with the KO-to-WT tissue. Scale bar, 100 μimmunoreactivity as compared with the KO-to-WT tissuLab Invest.
Figure 3
Figure 3
TRPA1 antagonist (HC-030031) treatment improves alkali burn-induced wound healing response in wild-type (WT) mice. (A) In WT mice, wound healing progression is compared at 5, 10 or 20 days after injury in the presence and absence of HC-030031. At each time point, corneal transparency restoration is markedly improved in the mice treated with this antagonist. At day 20, corneal transparency is restored in an antagonist treated mouse, but not in an untreated mouse. (B) The immunohistochemical staining patterns and the H&E stained histology are shown of burned corneas at day 10. The stromal organization is more poorly preserved in the untreated mice than in the antagonist treated mice. The infiltration levels of MPO-labeled neutrophils and F4/80-positive macrophages are lower in the antagonist treated mice than in the untreated counterpart. Similarly, the αhe immunohistochemicastaining are also less in the antagonist treated cornea than in their untreated counterpart. Scale bar, 100 Lab Invest.
Figure 4
Figure 4
Alkali burn injury activates TRP signaling and induces inflammatory/fibrogenic responses in mouse corneas. TRPV1 and TRPA1 transactivation of transforming growth factor (TGF)β1 -linked signaling induces fibroblasts to elicit fibrosis and inflammation - Interleukin-6 (IL-6)-induced fibrosis and inflammation are dependent on TRPV4 expression and activation in a severe injury model.
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