Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection.

Angela A S Sena,Tiffany Glavan,Irina Grishina,Satya Dandekar,Luiz R Goulart,Sumathi Sankaran-Walters,Guochun Jiang

doi:10.1038/srep31157

Abstract

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection.

Highlights

Pathways of systemic immune activation while influencing pathways immune anergy in the gut mucosa during inflammatory diseases
During chronic SIV infection (26wk), the ANXA1 expression remained significantly increased in peripheral blood (FC =+ 4.2, p < 0.05), as shown in Fig. 1A, and this data was further supported by our previous study of gene expression profiling in SIV infection using microarray analysis[5]
We previously reported that ANXA1 expression was altered in the gut of SIV-infected macaques[5]

Summary

Introduction

Pathways of systemic immune activation while influencing pathways immune anergy in the gut mucosa during inflammatory diseases. We sought to investigate changes in ANXA1 expression in both peripheral and gut mucosal compartments during the course of SIV infection and disease progression. Our data showed divergent ANXA1 gene expression patterns in peripheral blood and gut mucosa in vivo during primary acute and chronic stages of viral infection, which may be associated with chronic SIV-infection induced immune activation. Expression of ANXA1 was negatively correlated with pro-inflammatory cytokines and positively associated with anti-inflammatory response, which was corroborated by exogenous ANXA1 stimulation of peripheral and gut mucosal immune cells, suggesting that the endogenous ANXA1 signaling may be dysfunctional during SIV infection. Our data suggest that dysfunctional ANXA1 expression and signaling may impact the immune activation in periphery, and may impair the gut immune responses, leading to SIV disease progression

Methods

Results

Conclusion