bioRxiv : the preprint server for biologyOct 25, 2026

Daily cycle and sex differences in airway allergy reactions to Alternaria alternata

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 26, 2026

Abstract

Alternaria alternata exposure induces allergic airway inflammation and hyperresponsiveness in a circadian- and sex-dependent manner.

Female mice exhibited greater immune cell infiltration at Zeitgeber Time 0 (ZT0), while males showed stronger responses at ZT12.
IL-33 release and accumulation of certain immune cells varied by sex and time of day after exposure to Alternaria.
Cytokine and chemokine profiles revealed significant variations in Th2 and proinflammatory responses, with higher levels detected at ZT12 in females and ZT0 in males.
Markers of tissue injury followed a similar circadian pattern, indicating fluctuations in damage associated with Alternaria exposure.
Airway hyperresponsiveness was more pronounced during the resting phase, particularly in male mice.
Exposure to Alternaria disrupted epithelial junction proteins and altered the expression of key circadian clock proteins.

Simplified

Asthma severity and immune responses are regulated by circadian rhythms, yet the role of circadian timing in fungal allergen-induced airway inflammation remains poorly defined. Alternaria alternata , a clinically relevant fungal allergen, is strongly associated with severe asthma exacerbations and persistent airway dysfunction. Using a preclinical mouse model, we investigated whether pulmonary responses to Alternaria exposure are influenced by time of day and sex. We demonstrate that Alternaria induces allergic airway inflammation, airway hyperresponsiveness (AHR), and epithelial barrier disruption in a circadian- and sex-dependent manner. Female mice exhibited enhanced eosinophilic, neutrophilic, interstitial macrophage, and dendritic cell infiltration predominantly at Zeitgeber Time 0 (ZT0), whereas males showed stronger inflammatory responses at ZT12. Alternaria exposure increased IL-33 release and promoted ILC2 and Th2 cell accumulation, with distinct temporal patterns between sexes. Cytokine and chemokine profiling revealed robust Th2, proinflammatory, and Th17 responses that varied with exposure time, with higher responses at ZT12 in females and ZT0 in males. Markers of tissue injury, including lactate dehydrogenase and uric acid, followed similar circadian-dependent trends. Functionally, Alternaria -exposed mice displayed greater AHR during the resting phase, particularly in males. Additionally, Alternaria disrupted epithelial junctional proteins (E-cadherin and ZO-1) and altered expression of core circadian clock proteins CLOCK, BMAL1, and REV-ERBα. Mechanistically, peak inflammation coincided with enhanced STAT1, STAT3, and STAT6 activation. Collectively, these findings identify circadian timing and sex as key determinants of fungal allergen-induced airway inflammation and suggest chronotherapeutic approaches may improve asthma outcomes.

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Daily cycle and sex differences in airway allergy reactions to Alternaria alternata

Abstract

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