HnRNP-A2/B1promotes the inflammatory signaling cascade in infection models and autoimmune disease

The innate immune system is the first line of defense against pathogens; it functions through various pattern recognition receptors (PRRs) that recognize microbial products or danger signals leading to the activation of signaling pathways which initiate transcription of inflammatory genes. Activation of the innate immune response is essential to resolve infections, however, its dysregulation can result in pathological inflammation, contributing to an array of diseases, such as atherosclerosis, autoimmunity and cancer. Our understanding of the mechanisms and genes that regulate this response is not yet complete. We have recently found hnRNPA2/B1, a ubiquitous RNA processing protein, to be a promoter of inflammatory signaling in murine infection models. We designed a novel hnRNP-A2/B1 cKO mouse model in which hnRNP-A2/B1 is only deleted in cells of myeloid origin (macrophages and neutrophils) . We found that hnRNP-A2/B1 KO macrophages display a perturbed immune response state, where immune gene expression was dysregulated at baseline state and under stimulus in addition to pronounced changes in key inflammatory cytokine production upon stimulation with LPS. We also show an overall impairment in hnRNP-A2/B1 cKO mice pro-inflammatory cytokine production in serum and spleen in response in an endotoxic shock model using LPS. In addition, hnRNP-A2/B1 cKO mice were more susceptible to Salmonella infection and failed to effectively clear out the pathogen, they also displayed a persistent impairment in pro-inflammatory cytokine production. Antibodies against HnRNP-A2/B1 are prevalent in Rheumatoid Arthritis (RA) patients, and the involvement of this protein in RA pathogenesis and the inflammatory over-activation associated with these diseases is under studied. We silenced hnRNP-A2/B1 is RA fibroblast like synoviocytes (FLS) from RA patients and showed that hnRNP-A2/B1’s removal attenuated the inflammatory profile of these cells. Collectively, our results highlight the integral role macrophages play as essential responders in the innate response and as effective inflammatory mediators. We also underline hnRNP-A2/B1 as a novel modulator of the inflammatory cascade and a major contributor to the innate immune response to stimulus. We hypothesize that hnRNP-A2/B1 regulates immune genes and modulates their expression via changes in alternative splicing. This study will advance our understanding of how the inflammatory response is coordinated and help us better understand inflammatory and infectious diseases. Furthermore, this study will advance the field by shedding light on the functions of a poorly studied RNA processing protein that’s implicated in an array of biological processes and enhance our understanding of hnRNPs in general.