Role of LPS in the development of asthma and allergy caused by airborne allergens

LPS, the bacterial lipopolysaccharide that helps Gram-negative bacteria create cell walls, has long perplexed immunologists.

Many studies have shown that being exposed to LPS while being exposed to environmental allergens reduces the risk of acquiring asthma or allergic illness. Several other studies have found that the presence of LPS during exposure to environmental allergens enhances the development of asthma and other allergic diseases.

In a work published in Cell Reports, Beatriz León, Ph.D., and colleagues from the University of Alabama at Birmingham have untangled this Gordian knot. They describe a sequence of mechanical steps that lead to a startling conclusion: the allergen itself is the key to LPS boosting or inhibiting allergic reactions.

A better understanding of the mechanisms driving allergic illness sensitization could lead to new ways for controlling allergic airway disease, particularly asthma. Asthma affects around 300 million children and adults globally, with a rapid increase in developed countries since the 1960s.

The antagonistic mechanisms of LPS to promote or prevent allergy illness through activation or inhibition of T helper-2 immune cells were unravelled by León and her UAB colleagues.

Their findings, which describe specialised roles for immune cells known as classical monocytes and non-classical monocytes, are summarised here.

For starters, bacterial LPS's protective function requires the presence of cysteine protease enzymatic activity in an airborne allergen. In the presence of LPS, allergens that possess cysteine protease enzymatic activity, such as home dust mites or papain, a papaya enzyme, inhibit sensitization. Despite the presence of LPS, the German cockroach airborne allergen, which lacks cysteine protease activity, increases sensitization.

The cysteine protease causes non-classical monocytes in the lungs to create the cytokine GM-CSF, or granulocyte-macrophage colony-stimulating factor, by an unclear mechanism. LPS' ability to decrease T helper-2 responses to allergens like home dust mites is controlled by GM-CSF signalling.

"As a result, because LPS's protective benefits are dependent on GM-CSF, LPS's therapeutic effects are limited to allergens with cysteine protease activity," León explained.

LPS can encourage pathogenic T helper-2 cell responses in the absence of GM-CSF by promoting the trafficking of lung migratory dendritic cells into lung-draining lymph nodes, where they can aid in the initiation of an immune response. When non-classical monocytes produce GM-CSF, however, LPS and GM-CSF work together to differentiate classical monocytes into monocyte-derived dendritic cells, which then instruct migratory dendritic cells in the lungs to suppress T helper-2 cell allergic airway inflammation by producing interleukin-12.

"Our findings demonstrate that GM-CSF separates the opposing activities of LPS in priming allergen-specific T helper-2 cell responses," stated León. "As a result, different host sensitivities to GM-CSF and/or LPS, which might be impacted by genetic variety or environmental factors, can have a big impact on the risk of allergic sensitization. Understanding these relationships could lead to new therapeutic approaches for preventing and perhaps reversing allergy illness."

Different allergen sensitization in mice models, transcriptional analysis, and in vivo loss-of-function and gain-of-function tests were all part of the study, titled "GM-CSF synthesis by non-classical monocytes modulates antagonistic LPS-driven functions in allergic inflammation."