Zebrafish cutaneous injury models reveal that Langerhans cells engulf axonal debris in adult epidermis

Abstract

Somatosensory neurons extend enormous peripheral axons to the skin, where they detect diverse environmental stimuli. Somatosensory peripheral axons are easily damaged due to their small caliber and superficial location. Axonal damage results in Wallerian degeneration, creating vast quantities of cellular debris that phagocytes must remove to maintain organ homeostasis. The cellular mechanisms that ensure efficient clearance of axon debris from stratified adult skin are unknown. Here, we establish zebrafish scales as a tractable model to study axon degeneration in the adult epidermis. Using this system, we demonstrate that skin-resident immune cells known as Langerhans cells engulf the majority of axon debris. In contrast to immature skin, adult keratinocytes do not significantly contribute to debris removal, even in animals lacking Langerhans cells. Our study establishes a powerful new model for studying Wallerian degeneration and identifies a new function for Langerhans cells in maintenance of adult skin homeostasis following injury. These findings have important implications for pathologies that trigger somatosensory axon degeneration.

Rho-associated kinase regulates Langerhans cell morphology and responsiveness to tissue damage

“…15,20,21 Previously, we showed that zebrafish Langerhans cells engulf axonal debris following cutaneous axon degeneration via their dynamic dendrites. 13 To understand the basis for these dendrite dynamics in more detail, we used our established skin explant assay 13 to monitor Langerhans cell dendrite motility by collecting confocal z-stacks every 30 seconds. Zebrafish Langerhans cells express transgenes driven by the mpeg1.1 promoter.…”

“…Following skin explant, somatosensory axons in the skin undergo a stereotypical degeneration process known as Wallerian degeneration, resulting in large quantities of debris internalized by Langerhans cells. 13 We questioned if axon degeneration altered Langerhans cell dendrite number, surface area, or cell morphology. To track somatosensory axon debris following Wallerian degeneration, we used Tg(p2rx3a:lexA;LexAOP:mCherry) 29 (hereafter referred to as Tg(p2rx3a:mCherry)), a reporter expressed in skin-innervating adult dorsal root ganglion neurons.…”

“…[8][9][10][11] Additionally, live-cell imaging studies in zebrafish have identified macrophage-like roles for Langerhans cells locally within the epidermis, including engulfment of degenerating axonal debris and migration to sites of keratinocyte damage. 12,13 The mechanisms of how Langerhans cells quickly and efficiently respond to tissue damage are unknown. Langerhans cells extend thin membrane protrusions known as dendrites between neighboring keratinocytes and in close proximity to somatosensory axons.…”

“…Similar to mammals, the adult zebrafish epidermis contains dendritic Langerhans cells that intermingle with peripheral somatosensory axons and stratified layers of keratinocytes (Figure 1A). [11][12][13][24][25][26] In this study, we use the genetic and imaging advantages of zebrafish along with our previously established skin explant assay to better understand Langerhans cell dendrite morphogenesis, dynamics, and responses to several forms of tissue damage.…”

Shape dynamics and migration of branched cells on complex networks

“…Due to the constrains of the microenvironment, motile cells often need to navigate tissues and organs avoiding the surrounding obstacles [5]. In order to efficiently migrate, immune [6,7] and cancer [1,8] cells acquire branched morphologies that allow them to explore the microenvironment. Cell migration in complex geometries has been studied in different in vitro models using different geometries and types of confinement [9][10][11][12][13][14][15][16][17][18].…”