The Olfactory Organ Is Populated by Neutrophils and Macrophages During Early Development

Abstract

The immune system of vertebrates is characterized by innate and adaptive immunity that function together to form the natural defense system of the organism. During development innate immunity is the first to become functional and is mediated primarily by phagocytic cells, including macrophages, neutrophils, and dendritic cells. In the olfactory sensory system, the same sensory neurons in contact with the external environment have their first synapse within the central nervous system. This unique architecture presents a potential gateway for the entry of damaging or infectious agents to the nervous system. Here we used zebrafish as a model system to examine the development of the olfactory organ and to determine whether it shares immune characteristics of a host defense niche described in other tissues. During early development, both neutrophils and macrophages appear coincident with the generation of the primitive immune cells. The appearance of neutrophils and macrophages in the olfactory organs occurs as the blood and lymphatic vascular system is forming in the same region. Making use of the neurogenic properties of the olfactory organ we show that damage to the olfactory sensory neurons in larval zebrafish triggers a rapid immune response by local and non-local neutrophils. In contrast, macrophages, although present in greater numbers, mount a slower response to damage. We anticipate our findings will open new avenues of research into the role of the olfactory-immune response during normal neurogenesis and damage-induced regeneration and contribute to our understanding of the formation of a potential host defense immune niche in the peripheral nervous system.

The Olfactory Tract: Basis for Future Evolution in Response to Rapidly Changing Ecological Niches

“…In spite of these intriguing observations, few studies have examined the potential for a neural-vascular or peripheral “olfactory neurohaemal organ” within the olfactory sensory system. In zebrafish we have recently described the blood/lymphatic vasculature in the developing olfactory organ (Palominos and Whitlock, 2021 ; Palominos et al, 2021 ) that runs adjacent to the region we previously described as containing cell bodies of the TN-GnRH3 neurons (Whitlock et al, 2003 ; Gopinath et al, 2004 ; Whitlock, 2004 ). In zebrafish, the GnRH3 receptor is present in the adult OE as assayed by immunocytochemistry (Whitlock et al, 2006 ) and the isolation of GnRH3-receptor mRNA from olfactory organ tissues (Corchuelo et al, 2017 ).…”

“…Previously we have shown that zebrafish can make and maintain memories of odors experienced as juveniles and that this “olfactory imprinting” is associated with transcriptional changes within the olfactory organs (Harden et al, 2006 ; Whitlock, 2006 ; Calfun et al, 2016 ). The subsequent analysis of olfactory organ cell types led to the discovery of local neutrophils and macrophages/microglia in the olfactory organs of developing and adult zebrafish (Palominos and Whitlock, 2021 ; Palominos et al, 2021 ; Figure 2B ). These observations build on previous data showing the intimate association between the olfactory sensory and immune systems with macrophages and/or microglia in cultures of olfactory mucosa (Pixley, 1996 ), the major histocompatibility complex class I (MHCI) in the olfactory placode of the mouse (Chacon and Boulanger, 2013 ), and recombination activating gene (RAG) gene expression in the intact OE of zebrafish (Jessen et al, 2001 ).…”

The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective

“…In comparison to macrophage dominant tissue niches lung innate immune niche is predominated by neutrophils ( Figure 3C ). Analogous to this role recently phagocytic populations including neutrophils and macrophages were detected in sensory olfactory organ of zebra fish and both phagocytic population play important roles in lifelong neurogenesis of olfactory epithelia ( Palominos and Kathleen, 2021 ). Though macrophages have longer residence times in tissues, neutrophils also have been shown to co-adapt to tissue microenvironments and cater to tissue specific functions and support organ homeostasis highlighting their non-canonical roles beyond infection immunity.…”

The olfactory organ is a unique site for resident neutrophils in the brain

“…Previously we have shown that the lymphatic vasculature (LV) associated with the developing olfactory organs is evident at 14 days post fertilization (dpf) initiating in the ventrolateral side of the organ (Palominos and Whitlock, 2020). To better understand the LV system in the olfactory sensory system of the adult we dissected brains, with olfactory organs attached, from Tg(lyve1b:EGFP;OMP:RFP) animals (Fig.…”

“…We have shown that neutrophils populate the developing olfactory organ and use the blood vasculature to migrate to the olfactory organ in response to injury (Palominos and Whitlock, 2020). With the recent re-discovery of the CNS lymphatics in mammals and zebrafish (Bower and Hogan, 2018; Louveau et al ., 2015), we examined the extent of lymphatic vasculature in the adult olfactory organs and its association with blood vasculature.…”