Researchers at the Johns Hopkins University School of Medicine examined the dynamic interplay between the sensory and immune roles of the olfactory epithelium (OE), providing valuable insights into how this nasal tissue navigates its dual responsibilities and the consequences of chronic inflammation.

A review article, published Nov. 15 in Trends in Immunology, focuses on the dual nature of the OE, which is traditionally viewed as sensory tissue but also plays a crucial defensive role. Findings indicate the OE provides a crucial barrier for the immune system to protect the brain from harm, which can be negatively impacted due to long-term inflammation, injury or aging. Understanding the OE’s two functions and how this balance can be disrupted may have broad implications across different causes of smell loss and may provide insights into related conditions.

The OE, a thin layer inside the nose that is responsible for sense of smell, is composed of sensitive neurons — brain cells that live only in the nose — that require a specific environment to function correctly. One of these neurons — the dendrite — is exposed to the air, and the other end — the axon — is connected in the brain. The dendrite senses odor in the nose, causing the neuron to fire, then the axon transmits that signal to the part of the brain just above the OE, separated only by a thin layer of bone. This bone has many tiny holes, through which bundles of axons travel like little wires, relaying information about smells from the OE.

Communication between the nervous and immune systems within the OE allows the immune system to be notified of injury or danger, while also allowing the immune system to direct the OE to maintain its status as a defensive barrier.

Dr. Andrew Lane

“While this anatomic arrangement is critical for detecting odors, it is also a potential weak point in the body’s defense preventing infections or environmental toxins from reaching the brain,” says Andrew Lane, director of the Johns Hopkins Sinus Center and the article’s corresponding author. “When necessary, the immune system can be activated to enter this fragile tissue to fight and eliminate potential threats.”

The OE has specialized cells. While some sense odors, others produce mucus and immune molecules to neutralize airborne pathogens and environmental irritants. Under normal conditions, these two types of cells work together in a balance. However, when the immune system is on high alert, as during an infection or in response to an allergen, the immune system prioritizes defense over sense of smell. In response to inflammatory signals coming from immune cells, neurons and their connections to the brain are sacrificed to strengthen the thin barrier between the OE and the brain. Then, nonneuronal cells in the OE change their function to work with the immune system to defend the body.

Dr. Nicholas Rowan

“This reinforcement involves swelling, extra mucus production and immune activity, which can disrupt the delicate environment needed for smell-detecting neurons to function,” says Nicholas Rowan, associate professor of otolaryngology–head and neck surgery and co-author of the article. “It’s like locking down a city during a threat. Some normal operations stop temporarily to ensure safety.”

While resources are being redirected toward sustaining cells that comprise the immune barrier, the OE is not capable of producing the cells that transmit signals governing the sense of smell.

“As a result, patients may lose their sense of smell as the olfactory epithelium prioritizes defending the body from the threat,” says Mohammed Ullah, the article’s lead author. “Once the threat subsides, however, the olfactory epithelium can begin to regenerate neurons again, restoring olfaction.”

The neurons responsible for sense of smell in this delicately positioned and critical checkpoint for the immune system have supporting stem cells (basal cells) that form a structural framework to contain the neurons. Basal cells continuously create new neurons and supporting cells, therefore supporting the OE’s regenerative abilities.

This capacity for regeneration is also found in barrier linings of the skin and mucus membranes like the respiratory epithelium. Barrier surfaces such as these are designed to be exposed to the environment and bounce back from typical wear and tear while protecting the body from infection or repairing it after injury. Although much is known about how the skin barrier and mucus membranes guard against infection and interact with the immune system to fight infection and regenerate after injury, how the specialized olfactory mucus membrane balances its two roles has been largely unexamined until recent years.

Notably, the COVID-19 pandemic led to a rise in interest regarding the OE when it was learned that the SARS-CoV-2 virus enters the body by infecting the OE’s supporting cells. One of this infection’s notable symptoms is a loss of smell, which results from damage to the OE’s tissue framework and the neurons. The presence of the virus triggers the body’s simultaneous natural immune response to defend the barrier between the nose and brain to prevent brain damage or infection.

“One strategy of the immune response in the olfactory epithelium seems to be to sacrifice the sense of smell temporarily, unplugging the neurons from brain and not replacing them, while at the same time beefing up the supporting cells and basal cells to form a strong barrier that works in concert with the immune system.” says Lane. “As long as the basal cells remain, the body has the potential to regrow the neurons later and restore the sense of smell after the infection is over.”

Although this immune response is normal and beneficial to overall recovery and health, it is possible that the same neuroimmune cross talk that fights off infection could become detrimental if not well-balanced.

“COVID-19 highlighted how viruses can exploit the OE, leading to sudden and sometimes prolonged loss of smell,” says Rowan. “The immune response appears to play a key role — in mild cases, it clears the virus and smell function is restored. But in severe cases, or in the setting of a high viral load, we suspect that local reactions in the OE damage the OE, delaying recovery.”

Researchers say understanding neuroimmune interactions in the OE may provide new insights into how the sense of smell might be maintained and restored, as well as how the body defends against viruses such as SARS-CoV-2 that enter the body through this vulnerable part of the nose. These advancements could lead to improved treatment options for diseases of chronic inflammation, such as long COVID cases and chronic rhinosinusitis (CRS), in which ongoing inflammatory signals may hold the OE in a defensive state, preventing neuron regeneration.

CRS is a condition in which the body fails to stop its inflammatory response when appropriate, instead continuing to falsely detect a foreign threat that does not exist. This inflammation results in anosmia (loss of the sense of smell).

“The research in this field as it currently stands is beginning to shed light on the biological mechanisms underlying this disease process that highlight the olfactory epithelium’s role in CRS,” says Ullah. “While more investigation is necessary to pinpoint the exact pathways and signals that are responsible, current research efforts offer promising insights into potential targets for future therapies.”

Low level inflammation associated with aging may also impair the OE’s repair mechanisms. Memory immune cells that accumulate over time in the olfactory tissue after previous infections or injuries can also signal basal cells to defend the barrier to the brain instead of replacing neurons associated with the sense of smell, contributing to a decline in olfactory function.

“There is a growing body of literature that increasingly demonstrates the relationship between inflammation and unhealthy aging — this is no different for the sense of smell,” says Rowan. “It would be very interesting to investigate how therapies that target inflammation in older adults could impact the sense of smell, and potentially even thwart some of the smell loss associated with aging.”

Additional studies may focus on the neuroimmune cross talk that contributes to the OE’s balancing act.

“Studies are needed to elucidate which particular cells are communicating and what the specific signals are,” says Lane. “The major knowledge gap is in whether neuroimmune signaling can be exploited therapeutically to drive regeneration to restore the sense of smell.”

Closing this knowledge gap and others relating to neuroimmune interactions within the OE will better equip researchers and clinicians to address the growing burden of olfactory disorders caused by infection, inflammation and aging.

Funding regarding this review article was supported by National Institutes of Health grants R01 DC016106 and R01 DC020841 (A.P.L).

No authors report conflicts of interest.