A novel mechanism of fine-tuning inflammatory responses

   Inflammation is an important component of innate immunity and is quickly induced by the host upon pathogenic infection. Upon infection, innate immune cells, such as macrophages, use pattern-recognition receptors (PRRs), mainly Toll-like receptors (TLRs), to detect conserved microbial molecules termed pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) released from injured or dead cells. Then, innate immune cells mount a defensive response to clear pathogens or damaged cells and coordinate the adaptive immune response. However, the innate immune response must be spatially and temporally controlled to avoid excessive inflammation.

   Among PRRs, TLR4 plays a central role in the recognition of both Gram-negative and Gram-positive bacteria. Upon TLR4 engagement, a serial of protein kinase cascades, including IκB kinase (IKK) and mitogen-activated protein kinase (MAPK), are activated to induce the production of pro-inflammatory cytokines, chemokines, and type I interferons. However, despite extensive investigation, the regulation of TLR4-mediated inflammatory responses remains unclear.

   A research group led by Dr. Li-Chung Hsu at the Institute of Molecular Medicine has been focused on studying the regulation of innate immunity and host responses against pathogenic infection and tissue damage. Hsu’s group recently identified an E3 ubiquitin ligase, ZNRF1, that modulates Caveolin-1 (CAV1, the major constituent of caveolae) ubiquitination and degradation, leading to regulation of TLR4-triggered inflammatory responses. Consistently, mice with deletion of ZNRF1 in their hematopoietic cells display increased resistance to endotoxic and polymicrobial septic shock due to attenuated inflammation. Mechanistically, ZNRF1-modulated CAV1 expression regulates Akt-GSK3b signaling; the downstream targets of this pathway inhibit inflammatory responses by suppressing induction of pro-inflammatory cytokines and enhancing production of anti-inflammatory cytokine IL-10. This study demonstrates that TLR4 activation induces a transient association between CAV1 and ZNRF1 as well as a decrease in CAV1 protein levels through the ubiquitin/proteasomal pathway to allow the inflammatory response to quickly shift toward pro-inflammatory cytokine/chemokine production. This shift is needed to constrain pathogens during the early phase of host infection.

   Sepsis caused by uncontrolled inflammation is the leading cause of death in intensive care units today. Numerous efforts have been made to develop therapeutic agents to block massive inflammation in septic patients, but these efforts have not yielded much success. In addition, chronic inflammation is mechanistically linked to numerous human diseases, including cancer and diabetes. Therefore, understanding the molecular mechanism of regulation of innate immunity has far reaching implications for the study of inflammation, cancer and infectious diseases. The study by Hsu’s group indicates that ZNRF1 is a novel regulator of TLR4-driven inflammation through controlling CAV1 protein levels. Moreover, excessive CAV1 expression has been shown to contribute to a variety of human diseases, including cancer metastasis and atherosclerosis. Thus, this finding suggests a novel therapeutic target for treatment of inflammatory and CAV1-related diseases.

Figure 1. (A) Immunofluorescence staining showing that ZNRF1 partially colocalizes with Caveolin-1. (B) The survival of Znrf1^∆ mice (dotted line, n=8) was longer than that of Znrf1^F/F mice (solid line, n=8) after cecal ligation and puncture. (C) The proposed model summarizing the control of Caveolin-1 protein levels and TLR-triggered immune responses by ZNRF1.

Reference
Chih-Yuan Lee, Ting-Yu Lai, Meng-Kun Tsai, Yung-Chi Chang, Yu-Hsin Ho, I-Shing Yu, Tzu-Wen Yeh, Chih-Chang Chou, You-Sheng Lin, Toby Lawrence, and Li-Chung Hsu (2017). The Ubiquitin Ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. Nature Communications, 8, 15502. DOI: 10.1038/ncomms15502

Associate Professor Li-Chung Hsu
Institute of Molecular Medicine
College of Medicine
lichunghsu@ntu.edu.tw

Clinical Assistant Professor Chih-Yuan Lee
Department of Surgery
National Taiwan University Hospital
gs2119@yahoo.com.tw

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