Sex Differences in IL-33-Induced STAT6-Dependent Type 2 Airway Inflammation

Abstract

Sex differences in asthma prevalence are well-documented but poorly understood. Murine models have contributed to our understanding of mechanisms that could regulate this sex disparity, though the majority of these studies have examined responses present after Th2 adaptive immunity is established. We have now investigated how sex influences acute activation of innate cell populations in the lung upon initial exposure to the model antigen, ovalbumin (OVA), in the presence of IL-33 (OVA+IL-33), to prime the lungs for type 2 immunity. We also examined how inflammatory responses induced by OVA+IL-33 were altered in mice lacking the STAT6 transcription factor, which is activated by IL-13, an effector cytokine of IL-33. Our data demonstrate that type 2 inflammation induced by OVA+IL-33 was more severe in female mice compared to males. Females exhibited greater cytokine and chemokine production, eosinophil influx and activation, macrophage polarization to the alternatively activated phenotype, and expansion of group 2 innate lymphoid cells (ILC2s). While increases in ILC2s and eosinophils were largely independent of STAT6 in both males and females, many other responses were STAT6-dependent only in female mice. Our findings indicate that a subset of type 2 inflammatory responses induced by OVA+IL-33 require STAT6 in both males and females and that enhanced type 2 inflammation in females, compared to males, is associated with greater IL-13 protein production. Our findings suggest blunted IL-13 production in males may protect against type 2 inflammation initiated by OVA+IL-33 delivery to the lung.

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

“…Moreover, female mice were more sensitive to OVA, based on diarrhea score, allergy score, and serum OVA-IgE levels. Previous studies have shown that blunted IL-13 production in males may protect against OVA-A and that a reduced percentage of Treg cells in female mice is important for the development of the OVA allergic immune response. , As the mortality of mice increased with more than five OVA-A, we suggest that female mice should be intraperitoneally injected four times with 50 μg of OVA to successfully establish an OVA-sensitive mouse model.…”

Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

“…This indicates a potential increased responsiveness of female AMs to comparable levels of IL-33, 31 which is supported by female biases in the response to exogenous IL-33 administration. 64 In order to determine whether any of the observed differences between sexes were due to differential uptake of MWCNT, phagocytosis was measured by flow cytometry; side scatter (SSC) values are reported to be proportionate to the relative amount of nanoparticles phagocytosed by cells. [65][66][67][68][69] The AM SSC observed at both 24 h and 7 days post-MWCNT exposure were not significantly different between sexes (Figure 1C).…”

Effectiveness of Indonesian house dust mite allergenic extract in triggering allergic rhinitis sensitivity in a mouse model: A preliminary study

“…Sex selection of experimental animals needs to be based on the goals and limitation that exists in a particular sex [16,17]. In AR conditions, several studies [18][19][20] have shown a higher sensitivity in showing allergic responses in female mice compared to males, as evidenced by the higher concentrations of pro-inflammatory cytokines produced. This is the main reason for using female sex to see the molecular responses more clearly.…”