WANG Honglin's group revealed the presence of "autoantigens" in the epidermal keratinocytes of patients with psoriasis and provided a new treatment strategy
Source：WANG Honglin
2020-09-17
On July 14, 2020, WANG Honglin group from Shanghai Jiao Tong University School of Medicine published a research paper entitled "Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis" in Immunity.
Psoriasis is a common chronic inflammatory skin disease, which is incurable, always relapses, and seriously impacts the physical and mental health of patients. It is listed as one of the world's top 10 persistent diseases by WHO. The global incidence of psoriasis is 1-3%, and the number of patients with psoriasis in China has reached 10 million. It is generally believed that psoriasis is caused by the auto-inflammatory reaction driven by the abnormal interplay between epidermal keratinocytes and skin immune cells. A large number of clinical studies have shown that the comorbidities of psoriasis include a variety of metabolic disorders and cardiovascular diseases, and the notion that psoriasis is a systemic disease is now widely recognized and accepted. Hence, psoriasis itself is not fatal, but its long-term complications can be life-threatening. Antibody drugs including anti-TNF, anti-IL-17A/IL-17R, and anti-IL-23 have good expectations and effects in the treatment of psoriasis by targeting the immune system and related factors. However, these drugs may cause opportunistic infections, and psoriasis tends to rebound after drug withdrawal. Therefore, in-depth research on the pathogenesis of psoriasis and new targets and strategies for treatment are imperative. The unresolved scientific questions in this field are: 1. What is the immunological basis for the immune system to "attack" keratinocytes, and are there "autoantigens" in keratinocytes? 2. Can direct targeting of keratinocytes relieve psoriasis?
The study first uncovered that the expression of serine/threonine phosphatase-6 (PP6) in psoriatic keratinocytes was significantly reduced, suggesting that the abnormal expression of PP6 may be involved in the development of psoriasis. The researchers further found that mice with Pp6 specifically ablated in keratinocytes spontaneously develop psoriasis-like skin inflammation which highly resembled human psoriasis. Pp6 deficiency in keratinocytes led to increased arginase (Arg1) and accumulation of urea cycle-associated metabolites including polyamines. Together with RNA-binding peptides, polyamines formed complexes with self-RNA released by keratinocytes and protected self-RNA from degradation. The "polyamine-self-RNA-cargo peptide" complex promoted self-RNA to be endocytosed and sensed by myeloid dendritic cells (DCs), which further released pro-inflammatory cytokines to drive skin inflammation. Topical application of an arginase inhibitor significantly improved the skin inflammation in mouse and non-human primate (NHP) models of psoriasis. The study revealed for the first time that the abnormal accumulation of metabolites caused by tissue-specific metabolic adaptations is an important "accomplice" to the occurrence and development of chronic inflammatory diseases such as psoriasis; the "polyamine-self-RNA-cargo peptide" complexes turn as a "self-antigen" that activates the skin immune responses; targeting arginine metabolism pathways of keratinocytes is expected to become a new strategy for the treatment of psoriasis.
The study was supported by Professor Florent Ginhoux from Singapore Immunology Network (SIgN), Professor Chen Xiang from Xiangya Hospital of Central South University, Professor Gu Jun from Shanghai Tenth People's Hospital, Professor Shi Yu-Ling from Shanghai Skin Disease Hospital, Professor Tao Wufan from Fudan University, and Dr. Wu Zhouwei from Shanghai General Hospital. The research was supported by National Science Fund for Distinguished Young Scholars, National Natural Science Foundation General and Youth Projects, Shanghai Collaborative Innovation Center for Translational Medicine project, and Shanghai High-Level Local University Innovation Research Team Program.
WANG Honglin group focuses on the research of skin immune disorders and skin stem cell biology and has achieved a series of innovative findings in the field of basic and translational research of psoriasis. Their recent achievements include: 1. The discovery that RNA virus infection but not streptococcal infection induces the occurrence and development of psoriasis. This is an important breakthrough in the etiology of psoriasis and provides new ideas for the active prevention and treatment of psoriasis; 2. The development of a small molecule drug candidate that selectively inhibits Th17 cell differentiation. The team owns the global intellectual property rights of this compound and has obtained 2 national invention patents and 1 PCT patent. This compound has been approved by the National Medical Products Administration (NMPA) for clinical trials and has started phase 1 clinical trial at Shanghai General Hospital. The compound is expected to become China’s first-in-class chemical drug for the treatment of psoriasis.
Links: https://www.cell.com/immunity/fulltext/S1074-7613(20)30234-X
Psoriasis is a common chronic inflammatory skin disease, which is incurable, always relapses, and seriously impacts the physical and mental health of patients. It is listed as one of the world's top 10 persistent diseases by WHO. The global incidence of psoriasis is 1-3%, and the number of patients with psoriasis in China has reached 10 million. It is generally believed that psoriasis is caused by the auto-inflammatory reaction driven by the abnormal interplay between epidermal keratinocytes and skin immune cells. A large number of clinical studies have shown that the comorbidities of psoriasis include a variety of metabolic disorders and cardiovascular diseases, and the notion that psoriasis is a systemic disease is now widely recognized and accepted. Hence, psoriasis itself is not fatal, but its long-term complications can be life-threatening. Antibody drugs including anti-TNF, anti-IL-17A/IL-17R, and anti-IL-23 have good expectations and effects in the treatment of psoriasis by targeting the immune system and related factors. However, these drugs may cause opportunistic infections, and psoriasis tends to rebound after drug withdrawal. Therefore, in-depth research on the pathogenesis of psoriasis and new targets and strategies for treatment are imperative. The unresolved scientific questions in this field are: 1. What is the immunological basis for the immune system to "attack" keratinocytes, and are there "autoantigens" in keratinocytes? 2. Can direct targeting of keratinocytes relieve psoriasis?
The study first uncovered that the expression of serine/threonine phosphatase-6 (PP6) in psoriatic keratinocytes was significantly reduced, suggesting that the abnormal expression of PP6 may be involved in the development of psoriasis. The researchers further found that mice with Pp6 specifically ablated in keratinocytes spontaneously develop psoriasis-like skin inflammation which highly resembled human psoriasis. Pp6 deficiency in keratinocytes led to increased arginase (Arg1) and accumulation of urea cycle-associated metabolites including polyamines. Together with RNA-binding peptides, polyamines formed complexes with self-RNA released by keratinocytes and protected self-RNA from degradation. The "polyamine-self-RNA-cargo peptide" complex promoted self-RNA to be endocytosed and sensed by myeloid dendritic cells (DCs), which further released pro-inflammatory cytokines to drive skin inflammation. Topical application of an arginase inhibitor significantly improved the skin inflammation in mouse and non-human primate (NHP) models of psoriasis. The study revealed for the first time that the abnormal accumulation of metabolites caused by tissue-specific metabolic adaptations is an important "accomplice" to the occurrence and development of chronic inflammatory diseases such as psoriasis; the "polyamine-self-RNA-cargo peptide" complexes turn as a "self-antigen" that activates the skin immune responses; targeting arginine metabolism pathways of keratinocytes is expected to become a new strategy for the treatment of psoriasis.
The study was supported by Professor Florent Ginhoux from Singapore Immunology Network (SIgN), Professor Chen Xiang from Xiangya Hospital of Central South University, Professor Gu Jun from Shanghai Tenth People's Hospital, Professor Shi Yu-Ling from Shanghai Skin Disease Hospital, Professor Tao Wufan from Fudan University, and Dr. Wu Zhouwei from Shanghai General Hospital. The research was supported by National Science Fund for Distinguished Young Scholars, National Natural Science Foundation General and Youth Projects, Shanghai Collaborative Innovation Center for Translational Medicine project, and Shanghai High-Level Local University Innovation Research Team Program.
WANG Honglin group focuses on the research of skin immune disorders and skin stem cell biology and has achieved a series of innovative findings in the field of basic and translational research of psoriasis. Their recent achievements include: 1. The discovery that RNA virus infection but not streptococcal infection induces the occurrence and development of psoriasis. This is an important breakthrough in the etiology of psoriasis and provides new ideas for the active prevention and treatment of psoriasis; 2. The development of a small molecule drug candidate that selectively inhibits Th17 cell differentiation. The team owns the global intellectual property rights of this compound and has obtained 2 national invention patents and 1 PCT patent. This compound has been approved by the National Medical Products Administration (NMPA) for clinical trials and has started phase 1 clinical trial at Shanghai General Hospital. The compound is expected to become China’s first-in-class chemical drug for the treatment of psoriasis.
Links: https://www.cell.com/immunity/fulltext/S1074-7613(20)30234-X
