Nanogel Mediated Delivery of IL-10 to Reduce Inflammation by Maternal Macrophages During Obese Pregnancy

Abstract

Pediatric non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver condition that is closely associated with maternal obesity and maternal/paternal Western-style diet (WSD), a high fat, high sugar diet. Pediatric NAFLD leads to chronic inflammation in the offspring hematopoietic stem and progenitor cells, as well as the developing liver, which increases risk of developing nonalcoholic steatohepatitis (NASH) in childhood. Recent studies conducted primarily in mice have identified maternal and paternal metabolic health, as well as in utero exposures, as critical factors influencing developmental programming of metabolic diseases in offspring. These findings have emphasized that, while inflammation and metabolic dysfunction can be passed across generations, this developmental programming is potentially preventable if prophylactic therapeutics are given to the mother during pregnancy. Mechanistically macrophages, tissue-resident innate immune cells that are present in maternal endocrine organs and the placenta, regulate inflammation in maternal tissues and the placenta. Macrophage phenotype can shift between inflammatory and regenerative states, which are regulated by cytokine signaling. Although anti-inflammatory cytokines such as IL-10 have the potential to reduce inflammation by promoting a regenerative macrophage phenotype, therapeutic use of recombinant IL-10 is limited by its short half-life and off-target effects. To overcome these challenges, we hypothesized that conjugating IL-10 to nanogels would allow targeted cytokine delivery, prolonging its half-life in maternal tissues and the placenta while retaining the anti-inflammatory activity of IL-10. To test this hypothesis, we evaluated the uptake and sub-cellular distribution of nanogels in immortalized murine macrophages as well as evaluated the biological activity of IL-10-nanogel conjugates in bone marrow derived macrophages, relative to unconjugated recombinant cytokine. Additionally, the biodistribution of the IL-10-conjugated nanogels was assessed in pregnant mice. Nanogels were preferentially taken up into the cytoplasm of macrophages through lysosomes. Conjugation with IL-10 influenced the nanogel uptake and had anti-inflammatory activity on bone marrow derived macrophages from mice fed control diet and a high-fat, high-sugar diet Nash diet. Biodistribution in pregnant mice fed the same diets revealed placental accumulation comparable to published reports on targeted placenta delivery by binding peptides. This novel cytokine-conjugated nanogel shows promising anti-inflammatory activity and has the potential to prevent the development of metabolic diseases such as NAFLD through placental biodistribution.