Identification and function of a C3 hiIL-33 +fibroblast population in the lungs

Abstract

Abstract Complement component C3 is known to be predominantly expressed by epithelial and immune cells, however, we have found that fibroblasts are a primary source of C3 in murine and human lungs. Specifically, C3 is majorly expressed in adventitial fibroblasts. Moreover, we found that C3 hifibroblasts are characterized by the expression of IL-33. Further, C3 and IL-33 are not only markers of a novel subset of pulmonary adventitial fibroblasts but form a functional axis where C3 drives the expression of IL-33. As compared to other adventitial fibroblasts, this C3 hiIL-33 +subset is enriched for matrix genes, especially type I collagen (COL1A1). These cells require a functional C3− IL-33 axis to maintain their matrix identity. Impairing C3 not only reduces their ability to make collagen but guides them towards a lipofibroblast program characterized by lower collagen content and higher lipid accumulation. As we and others have published that C3 is a key driver of allergic airway inflammation, we wanted to understand how exposure to allergen affected C3 hiIL-33 +fibroblasts. Using a murine model of airway allergy, we observed a significant increase in the C3 hiIL33 +fibroblast population in lung samples from house dust mite (HDM)-treated mice compared to the PBS control group. Recently, IL-33 +fibroblasts were found to support ILC2 recruitment during helminth infection. As we have found C3 is critical to maintain IL-33 in these cells, we aim to understand if C3 hiIL-33 +fibroblasts participate in allergy by mediating cellular crosstalk with ILC2s and T cells during type 2 immune responses. Supported by grants from NIH R01AI27644 and the Johns Hopkins Catalyst Award to Dr. Stephane Lajoie.