Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway

Li, Xiangru; Hao, Zhenhua; Liu, Xiaorong; Li, Wei

doi:10.3389/fimmu.2020.01123

Cited by 14 publications

(13 citation statements)

References 63 publications

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“…Acute colon injury mice model was built by intraperitoneal injection (i.p.) with 10 mg/kg LPS (Sigma, Shanghai, China) for 24 h as described before ( 29 – 31 ). BRD4 inhibition was applied by i.p.…”

Section: Methodsmentioning

confidence: 99%

JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS

et al. 2021

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Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1β and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.

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Section: Methodsmentioning

confidence: 99%

JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS

et al. 2021

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“…In vitro , experiments show that FHR‐1 from stem cells protects the stem cells themselves as well as endogenous astrocytes (Shi et al, 2016). Very recently, Li, Hao, Liu, and Li (2020) reported that LPS infection significantly enhanced alternative pathway activity in a mouse model in which FHRE, the murine homologue of FHR‐1, had been knocked out. These data support a regulatory role for FHR‐1 during complement activation.…”

Section: Complement Activationmentioning

confidence: 99%

“…Three FHR proteins that are present in mice show a high degree of amino acid identity with mouse factor H (range, 85–100%) (Hellwage et al, 2006; Li, Hao, Liu, & Li, 2020) (Figure 4). The three proteins are termed FHRB, FHRE and FHRC.…”

Section: Mouse Factor H‐related Proteins (Fhrs)mentioning

confidence: 99%

Factor H‐related protein 1: a complement regulatory protein and guardian of necrotic‐type surfaces

Skerka

Pradel

Halder

et al. 2020

British J Pharmacology

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Factor H-related protein 1 (FHR-1) is a member of the factor H protein family, which is involved in regulating innate immune complement reactions. Genetic modification of the encoding gene, CFHR1 on human chromosome 1, is involved in diseases such as age-related macular degeneration, C3glomerulopathy, and atypical hemolytic uremic syndrome, indicating an important role for FHR-1 in human health. Recent research data demonstrate that FHR-1 levels increase in IgA nephropathy and ANCA vasculitis and that FHR-1 induces strong inflammation in monocytes on necrotic-type surfaces, suggesting a complement-independent role. These new results increase our knowledge about the role of this complement protein in pathology and provide a new therapeutic target, particularly in the context of inflammatory diseases induced by necrosis. This review summarizes current knowledge about FHR-1 and discusses its role in complement reactions and inflammation. Abbreviations: FHR-1, factor H-related protein 1; IgAN, IgA associated nephropathy or Berger's disease; AMD, age-related macular degeneration; C3G complement C3 glomerulopathy; aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H gene, SCR, short consensus repeat; RCA, regulator of complement activation; SLE, systemic lupus erythematosus; TCC, terminal complement complex; CRP, C-reactive protein. unclear function. Recent studies report different regulatory roles for FHR-1, both as an inhibitor of terminal complement pathway activation and as an inducer of complement by out-competing the inhibitor factor H for binding to C3b, as well as by inducing NLRP3 in monocytes. The two faces of FHR-1 suggest that the protein may act in a certain plasma concentration together with factor H to regulate complement on healthy surfaces, but that when FHR-1 concentrations increase it may also act as a deregulator and inducer of inflammation on necrotic-type surfaces. Further studies will reveal more information about the plasticity of this protein.

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“…More specifically, the mCFHR genes differ in structure, domain composition, and sequence from the human genes (32). Like the human FHR proteins, a total of five murine CFHR genes have been suggested (mCFHR-A, mCFHR-B, mCFHR-C, mCFHR-D and mCFHR-E) and evidence for four mFHR proteins (FHR-B, FHR-C, FHR-D and FHR-E) has been derived from mRNA transcripts isolated from mouse liver (48,(140)(141)(142)(143). However, altogether, this suggests that direct comparisons between the human and mouse FHR proteins is not informative and, therefore, any mouse FHR homologs need to be identified, if they exist, by functional studies before rodent models can be used to further study the role of the FH protein family in human health and disease.…”

Section: Limitations Of Animal Modelsmentioning

confidence: 99%

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

et al. 2021

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Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.

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Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway

Cited by 14 publications

References 63 publications

JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS

JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS

Factor H‐related protein 1: a complement regulatory protein and guardian of necrotic‐type surfaces

A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

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