UC Riverside

Type 2 immunity is classically associated with helminth defense and allergic inflammation, but also regulates tissue repair, extracellular matrix remodeling, and metabolic homeostasis. Environmental exposures can alter the magnitude and quality of type 2 immune responses, yet how these changes affect tissue outcomes across metabolic and inflammatory disease settings remains incompletely understood. This dissertation investigates how distinct environmental exposures reshape type 2 immunity and tissue remodeling using two models of Nippostrongylus brasiliensis induced inflammation.In a western diet induced obesity model, we examined whether transient helminth infection protects against metabolic dysfunction through the type 2 associated immunoregulatory protein resistin like molecule alpha, or RELMα. Wild type and RELMα deficient mice were fed a western diet and infected with N. brasiliensis after weight gain had developed. Helminth infection attenuated weight gain, improved glucose tolerance, and reduced adipocyte hypertrophy in wild type mice, whereas these effects were absent in RELMα deficient mice. Bulk RNA sequencing and digital cell quantification showed that RELMα supported infection associated adipose tissue reprogramming, including enrichment of eosinophils and M2 macrophages, induction of metabolic pathways, and suppression of extracellular matrix and fibrotic remodeling programs. In a parallel model of helminth induced lung inflammation, we investigated whether Δ9 tetrahydrocannabinol, or THC, alters host immune responses during type 2 inflammation. THC did not significantly alter infection associated weight loss, fecal egg burden, or adult worm burden, but restrained circulating eosinophils and monocytes, increased regulatory T cell frequencies, and reduced TNFα and IFNγ secretion following ex vivo splenocyte stimulation. Bulk RNA sequencing showed that THC shifted lung eosinophils and macrophage enriched cells away from inflammatory, chemotactic, fibrotic, and costimulatory programs and toward stress adaptive and metabolic transcriptional states. Together, these studies demonstrate that type 2 immunity is a flexible tissue regulatory program shaped by environmental context. Helminth induced RELMα promotes metabolic protection and limits extracellular matrix remodeling during western diet induced obesity, while THC changes the inflammatory quality of helminth induced type 2 immunity without altering parasite burden. Collectively, this work highlights environmental regulation of type 2 immune pathways as a determinant of tissue remodeling, inflammatory tone, and metabolic homeostasis.