| First Author | Pathak V | Year | 2024 |
| Journal | Proc Natl Acad Sci U S A | Volume | 121 |
| Issue | 41 | Pages | e2320034121 |
| PubMed ID | 39348530 | Mgi Jnum | J:359657 |
| Mgi Id | MGI:7750263 | Doi | 10.1073/pnas.2320034121 |
| Citation | Pathak V, et al. (2024) Modulation of diabetes-related retinal pathophysiology by PTX3. Proc Natl Acad Sci U S A 121(41):e2320034121 |
| abstractText | Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3(KO)), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3(KO) mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3(KO) retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-alpha-induced reactive gliosis, as PTX3(KO) retinal explants did not up-regulate GFAP in response to TNF-alpha. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment. |
