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Asthma is a chronic airway inflammatory disorder that demonstrates a strong clinical bias in females of reproductive age. In this study we evaluated group 2 innate lymphoid cells (ILC2) that play a now well-defined role in allergy and asthma. ILC2 are rare immune cells that demonstrate a strong activation bias in females compared to males in both mice and humans. We hypothesized that ILC2 would be highly activated in people with asthma as compared to healthy, sex-matched controls. Subjects with asthma were identified by medical records searching and confirmed through pre-clinic interviews regarding asthma diagnosis. Additional demographic and clinical data were collected from study questionnaires or retrospective chart review. Correlations were determined between immune activation and hormone levels for each study participant regardless of healthy or asthma status. Results showed that within the asthma groups, female Veterans had higher circulating blood neutrophils compared to males, and males had higher eosinophils compared to females by complete blood cell count. ILC2 trended upwards in male Veterans with asthma compared to female Veterans with asthma (p = 0.086). Females with asthma had a marked reduction in CRTH2+ ILC2 in comparison to healthy female controls. The numbers of ILC2 in correlation to ovarian hormones were determined to show a significant inverse correlation with estrogen levels and ILC2 suggesting that estrogen may suppress ILC2 abundance in circulation. Additional studies are necessary to determine whether this estrogen-effect extends to the lung and airways of people with asthma.

Asthma affects over 300 million people worldwide, with increasing rates annually. Males have higher asthma prevalence in adolescence, while females exhibit higher rates in adulthood. Reduced mucosal‐associated invariant T (MAIT) cells are found in severe asthmatic airway disease. We hypothesize MAIT cells modulate airway inflammation and are regulated by sex hormones through their cognate hormone receptors. We compared circulating MAIT cells and ex vivo MAIT cell activation with MR‐1 ligand in controls and asthmatic individuals. MAIT cells were significantly lower in asthmatic males and females compared to healthy controls. MAIT cells derived from male and female asthma patients exhibited higher levels of estrogen receptors (ERs) than those from sex‐matched healthy controls, and ex vivo treatment with estrogen significantly decreased IFN‐γ production in asthmatics. Estrogen treatment did not reduce IFN‐γ in MAIT cells from healthy individuals. To explore the effect of estrogen on MAIT cells, we used the murine Alternaria alternata challenge model. Adoptive transfer of G‐protein coupled ER (GPER‐1) antagonist (G36)‐treated MAIT cells into Rag1 knockout mice (Rag1 −/− ) increased A. alternata ‐induced inflammation compared to those receiving MAIT cells without GPER‐1 blockade. These findings suggest GPER‐1 as a novel target to reduce airway disease in the asthmatic population.

A prominent feature of diabetes mellitus is the inability of insulin to appropriately increase the transport of glucose into target tissues. The contributions of different glucose transport proteins to insulin resistance in rats with streptozotocin-induced diabetes was evaluated. A glucose transporter messenger RNA and its cognate protein that are exclusively expressed in muscle and adipose tissue were specifically depleted in diabetic animals, and these effects were reversed after insulin therapy; a different glucose transporter and its messenger RNA that exhibit a less restricted tissue distribution were not specifically modulated in this way. Depletion of the muscle- and adipose-specific glucose transporter species correlates with and may account for the major portion of cellular insulin resistance in diabetes in these animals.

Since the introduction of electronic cigarettes to the US market, e-cigarettes have been posited as a safe alternative to combustible cigarettes. We developed a preclinical animal model to determine whether transitioning to e-cigarette use after up to 16 weeks of daily exposure to combustible cigarette smoke (CS) could restore normal lung immune responsiveness to house dust mites (HDM). In these studies, CS exposed animals were randomly assigned to 6 groups. (1) CS-CS mice continued combustible cigarette exposure for an additional 7 or 16 weeks, and (2) CS-recovery mice were removed from cigarette smoking where they recovered without intervention. (3) CS-carrier mice transitioned to vaporized propylene glycol (30%) with vegetable glycerol (70%) (i.e. carrier). (4) CS-salt mice transitioned to e-vapor exposure containing nicotine salt (liquid nicotine in benzoic acid + carrier), and (5) CS-base mice transitioned to daily exposures to liquid nicotine + carrier containing e-vapors. (6) Room air exposed mice, that were not smoked or exposed to e-cigarette vapors, were included as controls. We hypothesized that transitioning from CS to either of the three e-cigarette exposures (base, salt or carrier) would restore eosinophil influx into the airways following intranasal HDM administration. Here we report that shorter (7 week) e-vapor exposure containing salt, base or carrier led to significant eosinophil responses following HDM challenge. In the 16-week model, CS-base and CS-salt exposed animals did not regain their HDM responsiveness when compared to controls. CS-carrier mice did regain partial responses to HDM at 16 weeks as indicated by an increase in eosinophils compared to control mice. Lung resident lymphoid cells support the influx of eosinophils following allergen exposure. As such we measured total T cells, B cells and group 2 innate lymphoid cells (ILC2) in the lungs of each of the treatment groups. ILC2 and CD4+ T cells were reduced, and B cells were increased in the lungs of CS mice compared to controls. Numerically, the transition to nicotine-salt increased the CD3+ T cell response but transitioning to the nicotine-base significantly reduced CD19 B cells. Additional studies showed that GM-CSF protein was increased in cultured ILC and in whole lung tissues of control mice compared to CS-carrier mice indicating plasticity of the ILC2 population. RNA microarray analyses identified significant increases in GM-CSF, CCL17 and CCL24 transcripts in alveolar macrophages following the transition from CS to carrier compared to control mice. In summary, the immunosuppressive effects of CS may be restored following short-term use of e-cigarettes, but chronic use of e-cigarettes may blunt pulmonary immunity similarly to traditional cigarette smoke.