Abstract
Resident macrophages reside in all tissues throughout the body and play a central role in both tissue homeostasis and inflammation. Although the inner ear was once believed to be “immune-privileged,” recent studies have shown that macrophages are distributed in the cochlea and may play important roles in the immune system thereof. Resident macrophages have heterogeneous origins among tissues and throughout developmental stages. However, the origins of embryonic cochlear macrophages remain unknown. Here, we show that the early development of resident macrophages in the mouse cochlea depends on yolk sac hematopoiesis. Accordingly, our results found that macrophages emerging around the developing otocyst at E10.5 exhibited dynamic changes in distribution and in situ proliferative capacity during embryonic and neonatal stages. Cochlear examination in Csf1r-null mice revealed a substantial decrease in the number of Iba1-positive macrophages in the spiral ganglion and spiral ligament, whereas they were still observed in the cochlear mesenchyme or on the intraluminal surface of the perilymphatic space. Our results demonstrated that two subtypes of resident macrophages are present in the embryonic cochlea, one being Csf1r-dependent macrophages that originate from the yolk sac and the other being Csf1r-independent macrophages that appear to be derived from the fetal liver via systemic circulation. We consider the present study to be a starting point for elucidating the roles of embryonic cochlear resident macrophages. Furthermore, resident macrophages in the embryonic cochlea could be a novel target for the treatment of various inner ear disorders.
Highlights
Congenital hearing loss, which occurs in approximately one in one thousand newborns, is one of the many burdensome congenital anomalies or disabilities [1]
At E9.5, neither ionized calcium-binding adapter molecule 1 (Iba1), CD68, nor F4/80-positive macrophages were observed around the otocyst (Figures 1A,D,G), whereas macrophage precursors labeled with Iba1, CD68, or F4/80 were observed in the yolk sac at E9.5 (Figures 1B,E,H)
The present study revealed that resident macrophages in mice emerge around the otocyst at as early as E10.5
Summary
Congenital hearing loss, which occurs in approximately one in one thousand newborns, is one of the many burdensome congenital anomalies or disabilities [1]. Cytomegalovirus (CMV) infection during the gestational period accounts for 15–21% of all congenital hearing loss cases [2]. A large number of children develop hearing loss via congenital CMV infection every year, the detailed pathophysiology of CMV infection in the auditory pathway, including the cochlea, has not been fully understood. No therapeutic treatment for congenital hearing loss due to prenatal viral infections, such as CMV or rubella virus, is currently present. To elucidate the pathophysiological mechanisms and develop effective methods for treating cochlear damage due to intrauterine infection, understanding the immune system of the inner ear, especially during the embryonic period, is essential. Recent studies have revealed the presence of immune-competent cells in the cochlea, which are referred to as resident macrophages in the cochlea [5, 6]. Tissue resident macrophages are distributed in virtually all tissues throughout the body and play a central role in both tissue homeostasis and inflammation, completing tissue-specific functions, and protecting the organs and tissue from infection [7, 8]
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